Tagraxofusp + Azacitidine for Acute Myeloid Leukemia

(TAGALONG Trial)

Recruiting at 6 trial locations

Overseen By Gabrielle Tiggs

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Joshua Zeidner

Must be taking: Hypomethylating agents

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: Intensive chemotherapy, CNS involvement, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

53 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for individuals with acute myeloid leukemia (AML), a type of blood cancer. It tests a combination of two drugs, tagraxofusp (a diphtheria toxin-IL-3 fusion protein targeting the IL-3 receptor) and azacitidine, to determine their effectiveness in reducing cancer cells in the blood or bone marrow. The trial adjusts drug combinations based on patient response over up to 12 cycles, each lasting 28 days. Individuals recently diagnosed with AML who have not yet started treatment, particularly those whose leukemia cells test positive for CD123, may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, certain medications like hydroxyurea and cyclophosphamide must be stopped at least 12 hours and 5 days before starting the trial treatment, respectively. It's best to discuss your specific medications with the trial team.

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

Research has shown that tagraxofusp is generally safe, and its side effects can be managed. Since its approval in the U.S. for treating certain blood cancers, studies have closely monitored its effects. This approval indicates its safety for humans, though, like any medication, it may cause side effects.

Azacitidine treats blood disorders such as MDS (myelodysplastic syndromes) and AML (acute myeloid leukemia). It is considered safe and well-tolerated, though some patients have experienced side effects. While effective, azacitidine can sometimes cause adverse reactions.

Both treatments have been studied separately and together, yielding positive safety results. Discuss any concerns with the study team or a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Tagraxofusp is unique because it targets a specific protein called CD123, which is often found on leukemia cells but not on most healthy cells. This targeted approach is different from standard chemotherapy treatments, which attack rapidly dividing cells but can also harm healthy cells. Researchers are excited about tagraxofusp because it offers a more precise method of attacking leukemia cells while potentially sparing healthy ones, which could lead to fewer side effects. Additionally, tagraxofusp is combined with azacitidine to enhance its effectiveness, offering new hope for those with acute myeloid leukemia.

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

Research shows that tagraxofusp has potential in treating certain blood cancers. The FDA approved it for a rare type of leukemia because it targets and kills cancer cells with a marker called CD123. Studies have shown it can improve outcomes for patients with hard-to-treat leukemia. In this trial, participants will receive tagraxofusp, and depending on their response, some may also receive azacitidine. Azacitidine has proven effective in helping patients with high-risk acute myeloid leukemia (AML) live longer. It works by slowing the growth of cancer cells and helps prevent the disease from worsening. Together, tagraxofusp and azacitidine might form a strong combination for fighting AML. ^{6 7 8 9 10}

Who Is on the Research Team?

Joshua Zeidner, MD

Principal Investigator

University of North Carolina, Chapel Hill

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed, untreated Acute Myeloid Leukemia (AML) who have had at least two cycles of treatment with hypomethylating agents for certain blood disorders. Participants must have CD123 positive leukemia cells, a white blood cell count under 30 x 109/mL, be in relatively good health (ECOG Performance Status of 0-2), and have proper organ function and heart performance. Women must not be pregnant and all participants should agree to use contraception.

Inclusion Criteria

I am able to get out of my bed or chair and move around.

Written informed consent and HIPAA authorization for release of personal health information

I have been diagnosed with AML and have not started treatment.

Exclusion Criteria

Treatment with investigational drug within 14 days of study entry

I am willing and able to undergo intensive chemotherapy.

I do not have any severe health or mental conditions that could make this study unsafe for me.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Cycle 1-2

Tagraxofusp administered at 12 mcg/kg IV daily for 5 consecutive days over a 28-day cycle

8 weeks

5 visits (in-person) per cycle

Treatment Cycle 3-12

Continuation of tagraxofusp with or without azacitidine based on response, up to 1 year

10 months

5 visits (in-person) per cycle for tagraxofusp only; 10 visits (in-person) per cycle for tagraxofusp + azacitidine

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Tagraxofusp

Trial Overview The study tests Tagraxofusp administered intravenously over several cycles alongside Azacitidine for patients without complete remission after initial treatment. The first two cycles are shorter (21 days each), followed by up to ten more cycles every 28 days depending on the patient's response. Venetoclax may also be added if needed.

How Is the Trial Designed?

Group I: Experimental Group Experimental Treatment 3 Interventions

During Cycle 1 and Cycle 2: Tagraxofusp will be administered intravenously (12 mcg/kg) on days 1-5 of Cycle 1-2 (Cycle is 21 days) During Cycles 3-12: Subjects with a marrow CR after Cycle 2 will continue tagraxofusp ONLY for Cycles 3-12 (up to a year of treatment) on Days 1-5 of a 28 day cycle. For subjects without a marrow CR, azacitidine will be administered intravenously (75 mg/m2) on days 1-7 of Cycle 3-12 (Cycle is 28 days) and tagraxofusp will be administered intravenously (12 mcg/kg) on days 1-3 of Cycle 3-12 (Cycle is 28 days). Subjects who achieve a marrow CR receiving tagraxofusp only after Cycle 4, will continue tagraxofusp at 12 mcg/kg IV for 5 consecutive days every 28 days until Cycle 12. Subjects who continue to achieve an overall response (CR, CRi, PR, MLFS, marrow CR) receiving tagraxofusp and azacitidine will continue tagraxofusp at 12 mcg/kg IV for 3 consecutive days and azacitidine 75 mg/m2 SQ or IV on Days 1-7 every 28 days until Cycle 12.

Tagraxofusp is already approved in United States, European Union for the following indications:

Approved in United States as Elzonris for:

• Blastic plasmacytoid dendritic cell neoplasm (BPDCN)

Approved in European Union as Elzonris for:

• Blastic plasmacytoid dendritic cell neoplasm (BPDCN)

Who Is Running the Clinical Trial?

Joshua Zeidner

Lead Sponsor

Trials

1

Recruited

50+

Stemline Therapeutics, Inc.

Industry Sponsor

Trials

24

Recruited

6,500+

Stemline Therapeutics, Inc.

Collaborator

Trials

24

Recruited

6,500+

University of North Carolina, Chapel Hill

Collaborator

Trials

1,588

Recruited

4,364,000+

Published Research Related to This Trial

The genetically engineered diphtheria toxin GMCSF fusion protein (DTctGMCSF) showed superior efficacy compared to standard chemotherapy agents in treating acute myeloid leukemia (AML), achieving 60% long-term event-free survival in a mouse model.

DTctGMCSF was well-tolerated in cynomolgus monkeys at therapeutic levels, indicating potential safety for use in humans, especially for AML patients resistant to current treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo biotherapy of HL-60 myeloid leukemia with a genetically engineered recombinant fusion toxin directed against the human granulocyte macrophage colony-stimulating factor receptor. Perentesis, JP., Gunther, R., Waurzyniak, B., et al.[2013]

A new diphtheria toxin fusion protein, DT388IL-3, shows promise in targeting and killing leukemic blasts in acute myeloid leukemia (AML) while causing minimal harm to normal tissues, based on studies in nonhuman primates.

Variants of DT388IL-3, specifically DT388IL-3[K116W] and DT388IL-3[Delta125-133], demonstrated improved binding to IL-3 receptors and increased cytotoxicity against leukemia cell lines, suggesting they could be more effective treatments for chemotherapy-resistant AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diphtheria toxin fused to variant interleukin-3 provides enhanced binding to the interleukin-3 receptor and more potent leukemia cell cytotoxicity. Liu, TF., Urieto, JO., Moore, JE., et al.[2007]

The K116W variant of the DT(388)IL3 fusion protein demonstrated over 90% effectiveness in killing malignant progenitors from 17 out of 23 patients with acute myeloid leukemia (AML), while sparing normal progenitors, indicating its potential as a targeted therapy.

There is a strong correlation between the expression levels of IL-3 receptor subunits on AML cells and the effectiveness of the DT(388)IL3 variants, suggesting that measuring IL-3R expression could help identify patients who are most likely to benefit from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Variant diphtheria toxin-interleukin-3 fusion proteins with increased receptor affinity have enhanced cytotoxicity against acute myeloid leukemia progenitors. Hogge, DE., Yalcintepe, L., Wong, SH., et al.[2022]

Tagraxofusp, a targeted therapy for hematologic malignancies like AML and BPDCN, is effective primarily through its ability to ADP-ribosylate cellular targets, but resistance is linked to deficiencies in the diphthamide synthesis pathway rather than loss of CD123 expression.

Combining tagraxofusp with the DNA methyltransferase inhibitor azacitidine can restore sensitivity in resistant cells and enhance treatment efficacy, leading to a phase 1 clinical study of this combination in patients with myeloid malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance. Togami, K., Pastika, T., Stephansky, J., et al.[2021]

SL-401, a genetically engineered diphtheria toxin fused with interleukin-3, has demonstrated strong activity against blastic plasmacytoid dendritic cell neoplasm and shows promising response rates in various myeloid malignancies, including the ability to eliminate minimal residual disease.

Current clinical trials of SL-401 are yielding encouraging preliminary results, highlighting its potential as a targeted therapy for leukemia stem cell resistance, although challenges remain due to tumor mutational heterogeneity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies. Alkharabsheh, O., Frankel, AE.[2020]

In a phase 1b study involving 56 adults with CD123-positive acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), the combination of Tagraxofusp (TAG) with azacitidine (AZA) and the BCL-2 inhibitor venetoclax (VEN) showed promising efficacy, achieving a response rate of 69% in an expansion cohort of 26 patients, including a 39% complete remission rate.

The treatment was well-tolerated, with no increased toxicity observed from the combination therapy, and median overall survival was reported at 14 months, indicating that TAG-AZA-VEN is a safe and effective option for high-risk AML patients, including those with TP53 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia. Lane, AA., Garcia, JS., Raulston, EG., et al.[2023]

The DT(388)IL3 fusion protein showed potential efficacy in treating chemo-refractory acute myeloid leukemia (AML) and myelodysplasia (MDS), with 2 out of 40 AML patients achieving a complete remission and 1 out of 5 MDS patients achieving a partial remission.

The treatment was generally well-tolerated, with only transient side effects such as grade 3 transaminasemia and grade 2 fevers, indicating a favorable safety profile, but the infusion schedule may need adjustments to improve response rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia. Frankel, A., Liu, JS., Rizzieri, D., et al.[2019]

The novel fusion protein DT(388)IL3 showed significant anti-leukemia efficacy in an in vivo model, greatly prolonging disease-free survival (DFS) in mice with acute myeloid leukemia (AML) compared to control treatments, with DFS exceeding 120 days for intravenous administration.

DT(388)IL3 treatment resulted in only 10% mortality in mice, while other anti-leukemia agents also improved DFS, indicating that DT(388)IL3 could be a promising option for patients with chemo-resistant, IL-3 receptor positive AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diphtheria toxin-interleukin-3 fusion protein (DT(388)IL3) prolongs disease-free survival of leukemic immunocompromised mice. Black, JH., McCubrey, JA., Willingham, MC., et al.[2022]

Citations

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Clinical Utility of Azacitidine in the Management of Acute ... The data suggest that oral AZA maintenance is an effective maintenance strategy to prolong survival in high-risk as well as favorable-risk AML ...

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Clinical outcomes of AML patients treated with Azacitidine ... The AZA-001 phase III trial has demonstrated effectiveness of azacitidine (AZA) in a dose of 75 mg/m2 daily for 7 consecutive days in patients with high-risk ...

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Real-World Treatment Patterns and Outcomes with Oral ... At 12 mo, estimated OS and rwRFS rates from Oral-AZA initiation were 88.2% (standard error [SE], 2.3) and 85.5% (SE, 2.5), respectively. Median ...

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5-azacitidine prolongs overall survival in patients with ... Patients with intermediate-2 and high-risk myelodysplastic syndrome (MDS) have a survival rate of 0.4 to 1.2 years as well as a high risk of their disease ...

5. nature.com nature.com/articles/s41375-025-02730-3

Outcomes of patients treated with venetoclax plus ... The 5-year relative survival of patients with AML is ~32%, and survival rates are dependent on age at diagnosis. Patients <50 years of age have ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2948932/

Safety and efficacy of azacitidine in myelodysplastic ... Azacitidine has been reported to prolong survival in MDS patients. Azacitidine has been studied in different dosing schedules and combination therapies with the ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.7012

Updated efficacy and safety data from the AGILE study in ... IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival (OS), complete remission (CR), and CR or CR with partial ...

8. hematologyadvisor.com hematologyadvisor.com/news/azacitidine-myelodysplastic-syndrome-mds-adverse-events-safety-concerns/

New Adverse Events Highlight Safety Concerns With ... An analysis of 2 pharmacovigilance databases revealed a high prevalence of azacitidine-related adverse events in patients with MDS or AML.

9. ashpublications.org ashpublications.org/blood/article/110/7/2302/103627/Safety-and-clinical-activity-of-the-combination-of

Safety and clinical activity of the combination of 5-azacytidine ... We conducted a phase 1/2 study of the combination of 5-azacitidine (5-AZA), valproic acid (VPA), and ATRA in patients with acute myeloid leukemia or high-risk ...

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Maintenance Treatment with 5-Azacitidine in Patients ... Conclusions: Azacitidine is a safe and well-tolerated maintenance treatment option for AML patients unfit for intensive therapy following a ...