Tagraxofusp + Chemotherapy for AML

Overseen By Woo In (Yustina) Cho

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Stanford University

Must be taking: Venetoclax, Hypomethylating agents

Must not be taking: Immunosuppressive therapy

Disqualifiers: Significant cardiac disease, Uncontrolled infection, Active malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1-2 weeks

20 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received systemic anti-cancer therapy within 14 days before starting the study drugs, except for hydroxyurea during the first cycle if needed for disease control.

What data supports the effectiveness of the drug Tagraxofusp combined with chemotherapy for treating AML?

Research shows that Tagraxofusp, which targets a protein called CD123 found on many leukemia cells, has been effective in treating certain blood cancers. In a study, combining Tagraxofusp with other drugs led to positive responses in patients with high-risk acute myeloid leukemia, suggesting it could be a promising treatment option. ^{1 2 3 4 5}

Is Tagraxofusp safe for use in humans?

Tagraxofusp has been tested in clinical trials and shows encouraging safety in treating certain blood cancers, with expected side effects and no increased toxicity when combined with other drugs like azacitidine and venetoclax. ^{1 2 3 6 7}

What makes the drug Tagraxofusp unique for treating AML?

Tagraxofusp is unique because it targets the CD123 protein, which is overexpressed in many AML cases, using a fusion of interleukin-3 and diphtheria toxin to selectively kill leukemia cells while sparing normal cells. This targeted approach is different from traditional chemotherapy, which affects both cancerous and healthy cells. ^{1 2 3 5 6}

What is the purpose of this trial?

To determine the efficacy of the combination of tagraxofusp, cladribine, and cytarabine.

Eligibility Criteria

This trial is for individuals with a type of blood cancer called Acute Myeloid Leukemia (AML) that has come back or hasn't responded to treatment. Participants should have specific markers on their cancer cells (CD123-positive). Details about who can join are not fully provided, so interested persons should inquire further.

Inclusion Criteria

My albumin level is at least 3.2 g/dL without supplements.

No clinically significant abnormalities on 12-lead electrocardiogram (ECG) including: complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250ms, or QTcF (Friderica's method) >450ms in 3 successive measurements

Left ventricular ejection fraction ≥ 50%

Exclusion Criteria

I have lasting side effects from past treatments that are moderate to severe, except for hair loss, nausea, or tiredness.

I do not have active or suspected brain disease, confirmed by tests.

I am on immunosuppressive therapy, but only take 10 mg or less of prednisone daily.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tagraxofusp, cladribine, and cytarabine in various dose levels over a period of days

1-2 weeks

Daily visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

Treatment Details

Interventions

• Cladribine
• Cytarabine
• Tagraxofusp

Trial Overview The study is testing the effectiveness of combining a new drug, Tagraxofusp, with two chemotherapy drugs, Cladribine and Cytarabine. The goal is to see if this combination works better for treating AML than current treatments.

Participant Groups

Group I: Dose level 3 (DL3) Experimental Treatment 3 Interventions

DL3 will consist of cladribine 5mg/m2 IV once daily on days 1-5, cytarabine 20mg/m2 IV daily days 1-10, and tagraxofusp 12 mcg/kg IV daily days 4-6. If a DLT is encountered in the first 2 participants, 3 more will be enrolled at the same dose.

Group II: Dose level 2 (DL2) Experimental Treatment 3 Interventions

DL2 will consist of cladribine 5mg/m2 IV once daily on days 1-4, cytarabine 20mg/m2 IV daily days 1-7, and tagraxofusp 12 mcg/kg IV daily days 4-6. If a DLT is encountered in the first 2 participants, 3 more will be enrolled at the same dose.

Group III: Dose level 1 (DL1) Experimental Treatment 3 Interventions

DL1 will consist of cladribine 5mg/m2 IV once daily on days 1-3, cytarabine 20mg/m2 IV daily days 1-5, and tagraxofusp 12 mcg/kg IV daily days 4-6. If a DLT is encountered in the first 2 participants, 3 more will be enrolled at the same dose.

Group IV: Dose Level -1 (DL-1) Experimental Treatment 3 Interventions

DL -1 will consist of cladribine 5mg/m2 IV once daily on days 1-2, cytarabine 20mg/m2 IV daily days 1-4, and tagraxofusp 12mcg/kg IV daily days 4-6.

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

Approved in United States as Leustatin for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma
• Multiple sclerosis

Approved in European Union as Litak for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Stemline Therapeutics, Inc.

Collaborator

Trials

24

Recruited

6,500+

Stemline Therapeutics, Inc.

Industry Sponsor

Trials

24

Recruited

6,500+

Findings from Research

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]

CD123, a protein overexpressed in acute myeloid leukemia (AML) cells, is a promising target for new therapies due to its higher expression on leukemic cells compared to normal cells, making it a potential focus for treatment development.

Several CD123-targeting therapies, including tagraxofusp and flotetuzumab, have shown clinical promise, but overall efficacy remains unsatisfactory, indicating a need for improved strategies and combination treatments with other anti-leukemic drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD123 a Therapeutic Target for Acute Myeloid Leukemia and Blastic Plasmocytoid Dendritic Neoplasm. Pelosi, E., Castelli, G., Testa, U.[2023]

SGN-CD123A is a novel antibody-drug conjugate targeting the IL3 receptor alpha (CD123) that shows potent cytotoxic effects against 11 out of 12 CD123+ AML cell lines and 20 out of 23 primary AML patient samples, including those with challenging genetic profiles.

In preclinical models, SGN-CD123A not only eradicated AML in disseminated disease models but also achieved durable complete remission in patient-derived xenografts, indicating its potential as an effective treatment for AML patients resistant to conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of SGN-CD123A, A Potent CD123-Directed Antibody-Drug Conjugate for Acute Myeloid Leukemia. Li, F., Sutherland, MK., Yu, C., et al.[2020]

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]

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]

References

1. 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]

2. 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]

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

CD123 a Therapeutic Target for Acute Myeloid Leukemia and Blastic Plasmocytoid Dendritic Neoplasm. [2023]

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

Characterization of SGN-CD123A, A Potent CD123-Directed Antibody-Drug Conjugate for Acute Myeloid Leukemia. [2020]

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

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

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]