Tagraxofusp + Azacitidine for Acute Myeloid Leukemia

(TAGALONG Trial)

Recruiting at 3 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

Trial Summary

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.

What data supports the effectiveness of the drug Tagraxofusp + Azacitidine for Acute Myeloid Leukemia?

Research shows that combining Tagraxofusp with Azacitidine can restore sensitivity to treatment in resistant leukemia cells and has shown promising results in clinical trials, with a significant number of patients achieving positive responses, including those with high-risk genetic mutations. ^{1 2 3 4 5}

Is the combination of Tagraxofusp and Azacitidine safe for humans?

Tagraxofusp (also known as SL-401 or DT(388)IL3) has been tested in clinical trials for various blood cancers, showing some side effects like fever, chills, and low blood pressure, but generally with minimal toxicities. Azacitidine, also known as Vidaza, is a well-established treatment for certain blood disorders, and its safety profile is well-documented. ^{2 5 6 7 8}

What makes the drug Tagraxofusp unique for treating acute myeloid leukemia?

Tagraxofusp is unique because it combines a diphtheria toxin with interleukin-3 to specifically target and kill leukemia cells that overexpress the IL-3 receptor, which is common in acute myeloid leukemia. This targeted approach helps to minimize damage to normal cells and can overcome resistance to traditional chemotherapy. ^{1 3 5 6 7}

What is the purpose of this trial?

A treatment cycle is 28 days for Cycle 1 and Cycle 2. Tagraxofusp will be administered at 12 mcg/kg IV over 15 minutes (-5 or +15 minutes) daily for 5 consecutive days (or 5 doses over a period not to exceed 10 days if postponement is required to allow for toxicity resolution). Subjects with a marrow CR (See the protocol) after Cycle 2 will continue Tagraxofusp for Cycles 3 to 12 (up to 1 year of treatment) at 12 mcg/kg IV for 5 consecutive days every 28 days. In subjects without a marrow CR after 2 cycles of treatment, azacitidine 75 mg/m2 SQ or IV will be added on Days 1-7 every 28 days for up to 4 additional cycles of treatment. A treatment cycle is 28 days for Cycle 3 to Cycle 12. 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. Please see the protocol. Patients without an overall response to tagraxofusp + azacitidine after completion of 4 cycles of this combination will be discontinued from study treatment.

Research Team

Joshua Zeidner, MD

Principal Investigator

University of North Carolina, Chapel Hill

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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]

References

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

DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance. [2021]

2. United States 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. [2013]

3. Netherlands 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. [2007]

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

Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia. [2023]

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

Diphtheria toxin-interleukin-3 fusion protein (DT(388)IL3) prolongs disease-free survival of leukemic immunocompromised mice. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Variant diphtheria toxin-interleukin-3 fusion proteins with increased receptor affinity have enhanced cytotoxicity against acute myeloid leukemia progenitors. [2022]

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

Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia. [2019]