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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for individuals with relapsed or hard-to-treat acute myeloid leukemia (AML). Researchers aim to evaluate the effectiveness of combining three drugs—tagraxofusp (a diphtheria toxin-IL-3 fusion protein targeting the IL-3 receptor), cladribine, and cytarabine—in improving patient outcomes. The trial will explore various dosage levels to find the optimal balance of safety and effectiveness. It suits those with AML who have undergone a specific initial treatment and continue to face the disease. Participants must meet certain health criteria, such as maintaining a certain level of heart function and having no major heart blockages or active infections. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment combination.

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.

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

Research shows that tagraxofusp, when used alone, is generally safe. Most side effects are temporary and tend to lessen over time. Patients in other studies have usually found it manageable.

For cladribine, studies indicate it is safe and well-tolerated, especially in patients with acute myeloid leukemia (AML). It often improves survival rates.

Cytarabine is often used to treat various types of leukemia, including AML. While high doses can be hard on the body, lower doses are safe and effective.

Overall, researchers have studied each of these drugs for safety individually. The current focus is on how well they work together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Tagraxofusp combined with chemotherapy for treating acute myeloid leukemia (AML) because it offers a novel approach targeting the CD123 receptor. Unlike traditional AML treatments like daunorubicin and cytarabine, which primarily target rapidly dividing cells, Tagraxofusp is a fusion protein that specifically targets and binds to the CD123 receptor on leukemia cells, potentially leading to more precise and effective targeting of cancer cells. This new mechanism of action might reduce the off-target effects seen with conventional chemotherapy, offering hope for better outcomes and fewer side effects for patients.

What evidence suggests that this trial's treatments could be effective for AML?

Research has shown that tagraxofusp is promising in treating certain blood cancers, achieving high success rates. In some studies, tagraxofusp led to a complete response in 75% of patients. Cladribine has also proven effective, achieving complete remission in up to 71% of patients with acute myeloid leukemia (AML). Cytarabine, a well-known treatment for AML, results in complete remission in 60% to 80% of cases. This trial will explore different dose levels of these treatments combined to enhance their effectiveness against AML. Each treatment has succeeded individually, suggesting they could be even more powerful when used together in this study. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

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

Left ventricular ejection fraction ≥ 50%

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

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

Exclusion Criteria

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.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6549775/

Efficacy and toxicity of cladribine for the treatment ... Results: A total of 10 clinical trials including 422 refractory AML patients were analyzed. The overall CR rate was 42.2% (95% CI: 31.0–54.3%).

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0145212618300651

Acute myeloid leukemia induction with cladribine Complete remission (CR) occurred in 71%, with overall response of 79%. One-year survival overall was 59%, with 47% (27/57) among patients ≥60 years old ...

3. link.springer.com link.springer.com/article/10.1007/s00277-025-06389-9

Efficacy and safety of cladribine, low-dose cytarabine and ... The efficacy of the venetoclax-based regimen in R/R AML was not satisfactory, with a remission rate of 21% and a median survival of 3.0 months [ ...

4. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/3805/533951/Patient-Reported-Outcomes-in-Older-Acute-Myeloid

Patient-Reported Outcomes in Older Acute Myeloid Leukemia ... Addition of Cladribine to the Standard AML ... Improved Survival in Acute Myeloid Leukaemia Patients Aged over 40 Given Cladribine ...

5. tandfonline.com tandfonline.com/doi/full/10.1080/16078454.2021.1962047

Full article: Efficacy and safety of cladribine addition to ... The conclusion was that 58% of AML patients achieved CR after one course of treatment[Citation4]. Based on this, PALG published the results of a ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2012/020229s034lbl.pdf

LEUSTATIN (cladribine) Injection For Intravenous Infusion ... The following safety data are based on 196 patients with Hairy Cell Leukemia: the original cohort of 124 patients plus an additional 72 patients enrolled at ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11592422/

Cladribine-Based Therapy for Acute Myeloid Leukemia in ... It was found to be safe and well tolerated in these patients and also showed improved survival outcomes. About half of the patients responded to ...

8. bloodcancerstoday.com bloodcancerstoday.com/post/safety-data-for-triplet-combination-in-high-risk-mds-cmml

Safety Data for Triplet Combination in High Risk MDS, CMML Cladribine in combination with low dose cytarabine (LDAC) and venetoclax is safe to treat patients with high-risk myelodysplastic syndromes ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT03181815

Cladribine in Combination With CAG in Patients ... The vast majority of patients with AML will die of the disease, and no standard chemotherapy regimen were defined for patients with relapsed/refractory AML.