Axatilimab + Azacitidine for Myeloid Leukemia

Overseen By The Ohio State University Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Uma Borate

Must not be taking: Chemotherapy, Lenalidomide, HMAs

Disqualifiers: AML, Organ transplant, Myositis, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

52 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib/II trial tests the best dose of axatilimab and effectiveness of axatilimab with or without azacitidine for the treatment of patients with advanced phase myeloproliferative neoplasms (MPN), myeloproliferative neoplasm/myelodysplastic syndrome (MPN/MDS) overlap or high risk chronic myelomonocytic leukemia (CMML). Axatilimab is an antibody that is cloned from a single white blood cell that is known to be able to recognize cancer cells and block a protein on the surface of the white blood cells that may be involved in cancer cell growth. By blocking the proteins, this may slow or halt the growth of the cancer. Azacitidine is in a class of medications called antimetabolites. It works by stopping or slowing the growth of cancer cells. Giving axatilimab with or without azacitidine may be safe and effective in treating patients with advanced phase MPN, MPN/MDS overlap or high risk CMML.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, previous treatment with certain chemotherapy or antineoplastic agents is not allowed, except for up to 2 cycles of hypomethylating agents. Previous treatment with hydroxyurea and/or ruxolitinib is permitted.

What data supports the idea that Axatilimab + Azacitidine for Myeloid Leukemia is an effective treatment?

The available research does not provide specific data on the effectiveness of Axatilimab + Azacitidine for Myeloid Leukemia. However, it does show that azacitidine, when combined with other drugs like ivosidenib, can be more effective than azacitidine alone for treating acute myeloid leukemia. This combination tripled overall survival and increased complete remission rates. Azacitidine alone has shown to improve survival in some patients, but adding it to standard chemotherapy did not provide additional benefits. Therefore, while azacitidine is effective in some combinations, there is no direct evidence here for Axatilimab + Azacitidine. ^{1 2 3 4 5}

What safety data exists for the treatment of Axatilimab and Azacitidine in myeloid leukemia?

The safety data for Azacitidine, a key component of the treatment, is well-documented. In a study of 1406 patients receiving Azacitidine, common adverse events included grade 3-4 anemia (43.4%), thrombopenia (36.8%), and neutropenia (36.1%). Febrile neutropenia occurred in 33.4% of patients. Other adverse events included fatigue (33.4%), pain (29.2%), and pyrexia (23.5%). Treatment termination due to adverse events was rare (5.1%). Another study showed that Azacitidine reduced the incidence rates of treatment-emergent adverse events and related hospitalizations compared to conventional care regimens in older patients with AML. In combination studies, such as with durvalumab, no new safety signals emerged, and the safety profile was consistent with known data. Overall, Azacitidine has a well-established safety profile, and adverse events can be managed with prophylactic and concomitant medications. ^{1 6 7 8 9}

Is the drug Axatilimab a promising treatment for myeloid leukemia?

The information provided does not specifically mention Axatilimab, so we cannot determine if it is a promising treatment for myeloid leukemia based on the given data. ^{1 4 5 10 11}

Research Team

Uma Borate, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for patients with advanced myeloproliferative neoplasms, overlap of myelodysplastic syndrome and myeloproliferative neoplasm, or high-risk chronic myelomonocytic leukemia. Specific eligibility criteria are not provided but typically include factors like age, disease stage, and overall health.

Inclusion Criteria

Morphologically confirmed diagnosis of specific conditions based on 2016 World Health Organization (WHO) classification

Patient is able to communicate with the investigator and comply with study procedures

I am using effective birth control methods if capable of having children.

Exclusion Criteria

I have a history of myositis.

Participants with prior malignancy, except specific cases

Previous known allergy/sensitivity to components of axatilimab

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Patients receive axatilimab intravenously over 30 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Variable, based on disease progression

2 visits per cycle (in-person)

Phase II Treatment

Patients receive axatilimab IV over 30 minutes on days 1 and 15 and azacitidine IV over 10-40 minutes or subcutaneously on days 1-7 of each cycle. Cycles repeat every 28 days for up to 4 cycles, with potential extension up to 24 cycles based on response.

Up to 24 cycles

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 6 months for up to 24 months.

Up to 24 months

Regular follow-up visits

Treatment Details

Interventions

• Axatilimab
• Azacitidine

Trial Overview The trial is testing the effectiveness of axatilimab alone or combined with azacitidine in treating certain blood cancers. Axatilimab blocks proteins that may be involved in cancer growth; azacitidine slows down cancer cell growth.

Participant Groups

Group I: Phase II (Axatilimab and azacitidine) Experimental Treatment 5 Interventions

Patients receive axatilimab IV over 30 minutes on days 1 and 15 and azacitidine IV over 10-40 minutes or SC on days 1-7 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve PR or better may continue for up to 24 total cycles. Patients who achieve less than PR receive 2 additional cycles and, if PR or better is achieved, may complete up to 24 total cycles. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.

Group II: Phase I (Axatilimab) Experimental Treatment 3 Interventions

Patients receive axatilimab IV over 30 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. At time of phase Ib completion, patients with clinical improvement may transition to phase II. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.

Axatilimab is already approved in United States for the following indications:

Approved in United States as Axatilimab for:

• Chronic Graft-Versus-Host Disease

Who Is Running the Clinical Trial?

Uma Borate

Lead Sponsor

Trials

7

Recruited

310+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

In a phase 2 study involving 129 older patients with acute myeloid leukemia (AML), the combination of durvalumab (a PD-L1 inhibitor) and azacitidine did not show improved overall response rates or survival compared to azacitidine alone, with response rates of 31.3% for the combination and 35.4% for azacitidine alone.

The safety profile of the combination treatment was similar to azacitidine alone, with no new safety concerns identified, and the most common side effects were constipation and thrombocytopenia, indicating that while the combination is feasible, it does not enhance clinical efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for older patients with AML. Zeidan, AM., Boss, I., Beach, CL., et al.[2022]

A phase III study demonstrated that combining azacitidine with the IDH1 inhibitor ivosidenib significantly improves treatment outcomes for patients with acute myeloid leukemia who cannot undergo intensive chemotherapy.

The combination therapy tripled overall survival rates and enhanced complete remission and event-free survival compared to azacitidine alone, indicating a substantial efficacy boost from this drug pairing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivosidenib Boosts OS with Azacitidine in AML. [2022]

A phase 3 clinical trial and subsequent analysis of real-world data confirmed that azacitidine significantly improves median overall survival (OS) for patients with acute myeloid leukaemia (AML) with >30% bone marrow blasts and white blood cell counts ≤15 G/L, showing comparable results between trial participants and routine clinical practice.

The pooled analysis of 309 patients demonstrated a median OS of 10.3 months and a one-year survival rate of 45.8%, indicating that azacitidine is an effective front-line treatment for AML patients beyond those who meet strict clinical trial criteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine for Front-Line Therapy of Patients with AML: Reproducible Efficacy Established by Direct Comparison of International Phase 3 Trial Data with Registry Data from the Austrian Azacitidine Registry of the AGMT Study Group. Pleyer, L., Döhner, H., Dombret, H., et al.[2018]

Oral azacitidine (oral-Aza) significantly improves median overall survival in patients with acute myeloid leukemia (AML) in remission, with a survival of 24.7 months compared to 14.8 months for placebo, highlighting its efficacy as a maintenance therapy.

Preclinical studies show that extended exposure to oral-Aza leads to sustained loss of DNMT1, resulting in hypomethylation and differentiation of leukemic stem cells, which is partly driven by increased myeloperoxidase (MPO) expression, suggesting a novel mechanism of action for targeting these cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase. Jeyaraju, DV., Alapa, M., Polonskaia, A., et al.[2023]

In a trial involving 214 older patients with untreated acute myeloid leukemia (AML), adding azacitidine to standard chemotherapy did not improve event-free survival or overall survival compared to chemotherapy alone, with median overall survival being 15 months for the azacitidine group and 21 months for the chemotherapy-only group.

While the combination treatment resulted in higher toxicity, with more adverse events reported, it did not lead to a significant difference in early death rates, indicating that azacitidine may not be beneficial for unselected older patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia. Müller-Tidow, C., Tschanter, P., Röllig, C., et al.[2018]

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]

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]

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]

The combination of azacitidine with standard chemotherapy for older patients with acute myeloid leukemia (AML) was found to be feasible and did not result in dose-limiting toxicity, indicating it can be safely administered alongside traditional treatments.

Despite the initial promise, the trial was halted due to increased cardiac toxicity observed in the experimental arm, highlighting the need for careful monitoring of safety in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of azacitidine added to standard chemotherapy in older patients with acute myeloid leukemia--a randomised SAL pilot study. Krug, U., Koschmieder, A., Schwammbach, D., et al.[2021]

In a trial involving 70 patients with relapsed/refractory acute myeloid leukemia (AML), the combination of azacitidine and nivolumab resulted in an overall response rate of 33%, with particularly promising results in patients who had not previously received hypomethylating agents, achieving a response rate of 58%.

The treatment was generally safe, with only 11% of patients experiencing grade 3 to 4 immune-related adverse events, and pretherapy levels of CD3 and CD8 in bone marrow and blood were identified as potential biomarkers for predicting patient response to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study. Daver, N., Garcia-Manero, G., Basu, S., et al.[2020]

In the AZA-001 trial, azacitidine significantly improved survival in patients with high-risk myelodysplastic syndrome and acute myeloid leukemia, with 91 out of 179 patients responding to treatment after a median of 14 cycles.

Continued treatment with azacitidine beyond the first response led to an improved response category in 48% of patients, suggesting that ongoing therapy can enhance clinical benefits for those who initially respond.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Silverman, LR., Fenaux, P., Mufti, GJ., et al.[2022]

References

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

A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for older patients with AML. [2022]

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

Ivosidenib Boosts OS with Azacitidine in AML. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Azacitidine for Front-Line Therapy of Patients with AML: Reproducible Efficacy Established by Direct Comparison of International Phase 3 Trial Data with Registry Data from the Austrian Azacitidine Registry of the AGMT Study Group. [2018]

4. Italy pubmed.ncbi.nlm.nih.gov

Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia. [2018]

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

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]

8. 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]

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

Feasibility of azacitidine added to standard chemotherapy in older patients with acute myeloid leukemia--a randomised SAL pilot study. [2021]

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

Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study. [2020]

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

Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. [2022]