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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the optimal dose and effectiveness of axatilimab, alone or with azacitidine, for treating specific blood cancers, including advanced myeloproliferative neoplasms (MPNs) and certain high-risk leukemias. Axatilimab, an antibody, targets cancer cells, potentially slowing or stopping their growth. Azacitidine also slows cancer cell growth. Suitable candidates for this trial have advanced-stage MPNs or similar blood disorders and have not responded to standard treatments. As a Phase 1/Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering a unique opportunity to access potentially groundbreaking therapies.

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.

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

In earlier studies, axatilimab showed some safety concerns. Researchers found that higher doses of axatilimab increased the risk of side effects. As the amount of axatilimab in the body rises, the chance of experiencing side effects may also increase. Patients in these studies experienced varying levels of side effects, but overall, the treatment was generally well-tolerated.

Azacitidine, the other treatment in the trial, has been studied for its use in various blood disorders. Research has shown it helps patients with myelodysplastic syndromes, which are disorders caused by poorly formed or dysfunctional blood cells. While azacitidine does not significantly extend survival for all patients, it can still be beneficial when combined with other treatments.

Overall, the combination of axatilimab and azacitidine is suggested to be safe and possibly effective for certain blood-related cancers. However, it is important to note that this trial is in its early stages, and the treatments are still being tested for safety and effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about axatilimab for myeloid leukemia because it offers a new way to target the disease. Unlike traditional treatments that focus on killing cancer cells directly, axatilimab is an antibody that targets the CSF-1R pathway, which plays a role in the immune environment of tumors. This approach could potentially enhance the body's immune response against leukemia. Additionally, when combined with azacitidine in later phases, it may increase the effectiveness of treatment by working in synergy to disrupt cancer cell growth and survival.

What evidence suggests that this trial's treatments could be effective for advanced phase MPN, MPN/MDS overlap, or high risk CMML?

Research has shown that axatilimab holds strong potential for treating certain types of cancer. In studies, 74% of patients experienced a reduction in cancer symptoms, with improvements seen in about 1.5 months on average. Axatilimab blocks certain proteins on white blood cells that aid cancer growth, potentially slowing or stopping the cancer. In this trial, participants in the Phase I arm will receive axatilimab alone, while those in the Phase II arm will receive a combination of axatilimab and azacitidine. Azacitidine, a drug that also slows cancer growth, has already helped patients with myelodysplastic syndromes live longer, making this combination a promising option for treating advanced blood cancers. ^{1 2 5 6 7}

Who Is on the Research Team?

Uma Borate, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

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 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]

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 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 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]

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]

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]

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]

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]

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]

Citations

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Safety and Efficacy of Axatilimab at 3 Different Doses in ... Clinical benefit, as measured by reduction in mLSS score, was reported in 55%, 54%, and 36% of patients in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 ...

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Dr Kitko on Clinical Outcomes With Axatilimab According to ... For patients who received axatilimab at 0.3 mg/kg, the ORRs were 63.3% (95% CI, 43.9%-80.1%) in the prior CR/PR group (n = 30), 81.3% (95% CI, ...

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Efficacy and safety of axatilimab in chronic graft-versus- ... Axatilimab demonstrates robust clinical activity in refractory cGVHD. · Overall response rate reached 65 % in clinical trials. · 64 % of patients showed ...

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Syndax Announces Compelling Revuforj® (revumenib) and ... In clinical trials, DS occurred in 60 (25%) of 241 patients treated with Revuforj at the recommended dosage for relapsed or refractory acute ...

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Safety and Efficacy Results from AGAVE-201 (Axatilimab ... 74% overall response rate · Median time to response of 1.4-1.7 months · Median failure-free survival of approximately 11 months · Main adverse ...

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Safety and Efficacy of Axatilimab at 3 Different Doses in ... Karolina Faysman, RN, MSN, AOCNP, DNPc, highlights efficacy, safety, and patient-reported outcomes from the phase 2 AGAVE-201 trial ...

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Exposure‐Response Relationships for Axatilimab in ... Ten of 11 safety endpoints were associated with axatilimab exposure, with higher axatilimab exposure increasing the odds of adverse events.