Tagraxofusp for Blood Cancers

Recruiting at 30 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

Trial Summary

What is the purpose of this trial?

Tagraxofusp is a protein-drug conjugate consisting of a diphtheria toxin redirected to target CD123 has been approved for treatment in pediatric and adult patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). This trial aims to examine the safety of this novel agent in pediatric patients with relapsed/refractory hematologic malignancies. The mechanism by which tagraxofusp kills cells is distinct from that of conventional chemotherapy. Tagraxofusp directly targets CD123 that is present on tumor cells, but is expressed at lower or levels or absent on normal hematopoietic stem cells. Tagraxofusp also utilizes a payload that is not cell cycle dependent, making it effective against both highly proliferative tumor cells and also quiescent tumor cells. The rationale for clinical development of tagraxofusp for pediatric patients with hematologic malignancies is based on the ubiquitous and high expression of CD123 on many of these diseases, as well as the highly potent preclinical activity and robust clinical responsiveness in adults observed to date. This trial includes two parts: a monotherapy phase and a combination chemotherapy phase. This design will provide further monotherapy safety data and confirm the FDA approved pediatric dose, as well as provide safety data when combined with chemotherapy. The goal of this study is to improve survival rates in children and young adults with relapsed hematological malignancies, determine the recommended phase 2 dose (RP2D) of tagraxofusp given alone and in combination with chemotherapy, as well as to describe the toxicities, pharmacokinetics, and pharmacodynamic properties of tagraxofusp in pediatric patients. About 54 children and young adults will participate in this study. Patients with Down syndrome will be included in part 1 of the study.

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.

What data supports the effectiveness of the drug Tagraxofusp for blood cancers?

Tagraxofusp has shown significant effectiveness in treating a rare blood cancer called blastic plasmacytoid dendritic cell neoplasm (BPDCN), with many patients able to proceed to further treatment like stem cell transplantation. It has also demonstrated promising results in other blood cancers, including myeloid malignancies, by targeting specific cancer cells and reducing disease presence. ^{1 2 3 4 5}

Is Tagraxofusp safe for use in humans?

Tagraxofusp has a manageable safety profile with common side effects like elevated liver enzymes, low blood protein levels, swelling, and low platelet counts. The most serious risk is capillary leak syndrome, which can be life-threatening but may be managed with early detection and treatment. ^{1 2 3 6 7}

What makes the drug Tagraxofusp unique for treating blood cancers?

Tagraxofusp is unique because it is the first FDA-approved drug specifically targeting CD123, a protein overexpressed in certain blood cancers, using a fusion of interleukin-3 and a diphtheria toxin to kill cancer cells. It is particularly effective for blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare cancer with no previous standard treatment. ^{1 2 3 7 8}

Research Team

Adam Lamble, MD

Principal Investigator

Seattle Children's Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Tagraxofusp, the first CD123-targeted therapy and first targeted treatment for blastic plasmacytoid dendritic cell neoplasm. [2019]

2. Switzerland pubmed.ncbi.nlm.nih.gov

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

3. Spain pubmed.ncbi.nlm.nih.gov

Tagraxofusp, a novel CD123-directed cytotoxin to treat blastic plasmacytoid dendritic cell neoplasm. [2020]

4. England pubmed.ncbi.nlm.nih.gov

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

5. 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]

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

Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

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

8. England pubmed.ncbi.nlm.nih.gov

Tagraxofusp in myeloid malignancies. [2023]