Tagraxofusp for Blood Cancers

Recruiting at 31 trial locations

Overseen By Ellynore Florendo

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Therapeutic Advances in Childhood Leukemia Consortium

Must not be taking: Corticosteroids, Investigational drugs, Anti-cancer agents

Disqualifiers: CNS disease, Active infection, DNA fragility, others

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

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

Compensation: Varies

Number of Visits: 6

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called tagraxofusp for children and young adults with certain blood cancers that have not responded to previous treatments. Tagraxofusp is unique because it targets a specific protein (CD123) found on cancer cells, helping to kill them while sparing healthy cells. The trial has two parts: one tests tagraxofusp alone, and the other combines it with chemotherapy. It is designed for patients whose cancer has returned or not improved after treatment and whose cancer cells show the CD123 protein. As a Phase 1 trial, this research focuses on understanding how tagraxofusp works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but some medications can be continued up to 24 hours before starting the trial. These include hydroxyurea and certain 'maintenance-style' therapies like vincristine, oral 6-mercaptopurine, and oral methotrexate. 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 shows that tagraxofusp is generally well-tolerated by adults and children with certain blood cancers. The FDA has approved it for treating blastic plasmacytoid dendritic cell neoplasm (BPDCN), indicating its safety for use in people.

In earlier studies, some patients experienced side effects, but these were often manageable. Common side effects included fever, nausea, and low blood counts. Serious side effects occurred less frequently but did happen. The safety record for tagraxofusp in adults provides some confidence in its potential safety for children, although this trial specifically aims to gather more information about its effects in children.

In summary, while tagraxofusp has shown some side effects, its approval for certain cancers and past study results suggest it can be safely administered with careful monitoring. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Tagraxofusp for blood cancers because it offers a novel mechanism of action by targeting the IL-3 receptor, which is often overexpressed in certain blood cancer cells. Unlike traditional chemotherapy that broadly attacks rapidly dividing cells, Tagraxofusp specifically aims at cancer cells, potentially reducing damage to healthy cells and minimizing side effects. Additionally, its integration with other agents like azacitidine, fludarabine, and vincristine in various trial arms could optimize treatment effectiveness and enhance patient outcomes. This targeted approach may lead to quicker and more effective responses compared to existing treatments.

What evidence suggests that this trial's treatments could be effective for pediatric hematologic malignancies?

Research shows that tagraxofusp effectively targets certain cancer cells, particularly in blood cancers like blastic plasmacytoid dendritic cell neoplasm (BPDCN). Earlier studies demonstrated strong and lasting responses in BPDCN patients, leading to its approval for this condition. This treatment targets a protein called CD123, commonly found on cancer cells, allowing it to affect even non-dividing tumor cells. In this trial, participants in different treatment arms will receive tagraxofusp combined with other drugs. For example, one arm will combine tagraxofusp with azacitidine, another with fludarabine, and another with vincristine. These combinations have shown promising results and are generally safe. These findings suggest that tagraxofusp could effectively treat various blood cancers by precisely targeting cancer cells while sparing healthy ones. ^{1 2 4 5 6}

Who Is on the Research Team?

Adam Lamble, MD

Principal Investigator

Seattle Children's Hospital

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 1 to 21 with relapsed or refractory hematologic malignancies expressing CD123. Eligible participants include those with various types of leukemia, lymphoma, and myelodysplastic syndrome who have experienced multiple relapses or did not respond to at least two chemotherapy cycles. Patients must have adequate organ function and agree to use contraception if applicable.

Inclusion Criteria

I have undergone specific treatments like chemotherapy or stem cell transplant.

My leukemia has returned or is not responding to treatment, and more than 5% of my bone marrow cells are immature blood cells.

My heart, lungs, liver, kidneys, and bone marrow are working well.

Exclusion Criteria

I do not have a DNA fragility syndrome.

I do not have allergies to the drugs used in this study or specific infections.

I am not on varying doses of corticosteroids for my condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy Treatment

Participants receive Tagraxofusp monotherapy to assess safety and confirm the FDA approved pediatric dose

21 days

5 visits (in-person)

Combination Chemotherapy Treatment

Participants receive Tagraxofusp in combination with chemotherapy agents such as Azacitidine, Fludarabine, Cytarabine, and others to assess safety and determine the recommended phase 2 dose

28 days

Multiple visits (in-person) on days 1, 8, 15, and 22

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Tagraxofusp

Trial Overview The study tests Tagraxofusp alone and in combination with other chemotherapies (like Hydrocortisone, Dexamethasone) in pediatric patients. It aims to determine the safe dosage levels, describe side effects, understand how the drug works in the body, and improve survival rates for these cancers.

How Is the Trial Designed?

Group I: Part 2 - Cohort C Experimental Treatment 5 Interventions

Tagraxofsup -Days 1-5 Azacitidine -Days 1-5 IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy * Day 1 * Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator CNS2/3 IT Therapy * Days 1, 8, 15, and 22 * Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

Group II: Part 2 - Cohort B Experimental Treatment 6 Interventions

Tagraxofsup -Days 8-12 Dexamethasone -Days 1-5 Vincristine -Days 1, 8, 15, and 22 IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy * Day 1 * Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator CNS2/3 IT Therapy * Days 1, 8, 15, and 22 * Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

Group III: Part 2 - Cohort A Experimental Treatment 6 Interventions

Tagraxofsup -Days 4-8 Fludarabine -Days 1-5 Cytarabine -Days 1-5 IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy * Day 1 * Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator CNS2/3 IT Therapy * Days 1, 8, 15, and 22 * Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

Group IV: Part 1 Experimental Treatment 4 Interventions

Tagraxofusp -Days 1-5 IT Therapy (may include methotrexate, cytarabine, or triple IT) * Day 1 * Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator

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?

Therapeutic Advances in Childhood Leukemia Consortium

Lead Sponsor

Trials

21

Recruited

680+

Published Research Related to This Trial

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-erzs (formerly DT-IL-3) is a novel therapeutic agent that targets the CD123 receptor, showing a 90% overall response rate in frontline treatment and 67% in relapsed/refractory cases of blastic plasmacytoid dendritic cell neoplasm (BPDCN), leading to its approval as the first treatment for this rare cancer.

While tagraxofusp-erzs is effective, it carries a significant risk of capillary leak syndrome, which can be life-threatening, prompting a 'black box' warning from the FDA to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. Pemmaraju, N., Konopleva, M.[2022]

Tagraxofusp (SL-401) is the only FDA-approved therapy for blastic plasmacytoid dendritic cell neoplasm (BPDCN), showing promise in treating this rare malignancy where conventional chemotherapy has poor outcomes.

While tagraxofusp effectively targets BPDCN cells due to their overexpression of the IL-3 receptor, it carries a risk of capillary leak syndrome and other common side effects like increased liver enzymes and low platelet counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tagraxofusp for the Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): A Brief Report on Emerging Data. Beziat, G., Ysebaert, L.[2020]

Tagraxofusp (SL-401) has shown high efficacy and an acceptable safety profile in treating blastic plasmacytoid dendritic cell neoplasm (BPDCN), leading to its approval by the FDA and EMA for this aggressive cancer.

The drug is being explored for use in other myeloid malignancies with high CD123 expression, particularly in combination therapies like tagraxofusp-azacitidine-venetoclax, which may help overcome resistance to tagraxofusp.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tagraxofusp in myeloid malignancies. Bruzzese, A., Martino, EA., Labanca, C., 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]

Tagraxofusp is an effective treatment for blastic plasmacytoid dendritic cell neoplasm (BPDCN), showing significant efficacy and a manageable safety profile in patients, including those aged 2 and older.

While it can cause serious side effects like capillary leak syndrome, early recognition and intervention can help mitigate these risks, making it a promising option for patients who previously had no standard therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tagraxofusp, the first CD123-targeted therapy and first targeted treatment for blastic plasmacytoid dendritic cell neoplasm. Economides, MP., McCue, D., Lane, AA., et al.[2019]

Tagraxofusp is a novel treatment for blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare and aggressive cancer, and it works by delivering a diphtheria toxin directly into cells that express the CD123 receptor, leading to cell death.

The FDA approved tagraxofusp on December 21, 2018, making it the first drug specifically approved for BPDCN, which historically has a poor prognosis with a median survival of only 9 to 13 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tagraxofusp, a novel CD123-directed cytotoxin to treat blastic plasmacytoid dendritic cell neoplasm. Tandon, A., Zhang, Y., Sokol, L.[2020]

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]

Citations

1. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/81/NCT04317781/Prot_SAP_000.pdf

Tagraxofusp (SL-401) therapy for blastic plasmacytoid ... BPDCN is a rare hematologic malignancy. The exact incidence is unknown because of changing nomenclature over time and a variety of clinical presentations.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6466259/

Clinical Activity and Tolerability of SL-401 (Tagraxofusp) Summary of SL-401 clinical trials in various hematologic neoplasms, baseline characteristics, adverse events and clinical outcomes (See page 14) ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1815105

Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm Tagraxofusp has shown potent antitumor activity against BPDCN cells in both in vitro and in vivo models, with cytotoxicity at femtomolar concentrations.

4. ashpublications.org ashpublications.org/blood/article/134/Supplement_1/558/426594/Results-from-a-Phase-1-2-Clinical-Trial-of

Results from a Phase 1/2 Clinical Trial of Tagraxofusp (SL-401 ... Tagraxofusp is a targeted therapy directed to CD123 that was approved by the FDA for the treatment of patients with blastic plasmacytoid ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.22.00034

Long-Term Benefits of Tagraxofusp for Patients With Blastic ... In first-line patients with BPDCN, TAG monotherapy resulted in high and durable responses, allowing many to bridge to stem-cell transplant.

6. ashpublications.org ashpublications.org/bloodadvances/article/4/16/4020/463447/Approval-of-tagraxofusp-erzs-for-blastic

Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic ... The modern, emerging field of targeting CD123/interleukin 3 (IL-3) receptor α (IL-3Rα) in hematologic malignancies may well be able to trace its ...