Tagraxofusp for Leukemia Maintenance Post-Transplant

Recruiting at 2 trial locations

Overseen By Samantha Brooks

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Karen Ballen, MD

Must not be taking: Prednisone, others

Disqualifiers: Active malignancy, CNS disease, 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: 1

Duration: 9 cycles (each cycle is 28 days)

44 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called tagraxofusp, a diphtheria toxin-IL-3 fusion protein targeting the IL-3 receptor, to help prevent leukemia from returning after a stem cell transplant. It targets patients with specific blood cancers such as myelofibrosis (MF), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) who are CD123+ (a marker on certain cancer cells). Participants will receive the treatment in cycles and undergo bone marrow tests to assess its effectiveness. Those who have already had a stem cell transplant and are in remission might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance 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 need to stop taking your current medications. However, you cannot have received any disease-related therapy, including radiation or investigational agents, within 14 days of starting the study.

Is there any evidence suggesting that tagraxofusp is likely to be safe for humans?

Research has shown that tagraxofusp, the treatment under study, has been used safely in other conditions. In past studies, patients who received tagraxofusp for conditions like blastic plasmacytoid dendritic cell neoplasm (a rare type of cancer) experienced manageable side effects. These side effects were not severe enough to outweigh the treatment's benefits.

In another study, tagraxofusp was used after stem cell transplants, and patients lived longer with manageable safety. This suggests that the treatment is generally well-tolerated when healthcare professionals closely monitor patients.

Since tagraxofusp is in a Phase 1 trial for this specific use, researchers are still studying its safety in this group of patients. However, earlier studies suggest that the treatment might be safe when used carefully. Always discuss the risks and benefits with a doctor if considering joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Tagraxofusp for leukemia maintenance post-transplant because it works through a unique mechanism of action. Unlike traditional treatments that target leukemic cells generally, Tagraxofusp specifically targets and binds to the interleukin-3 receptor, delivering a cytotoxic agent directly to the cells. This targeted approach has the potential to minimize damage to healthy cells and reduce side effects, offering a more precise and potentially safer treatment option for leukemia patients post-transplant. Additionally, its administration via intravenous infusion over specific cycles allows for controlled dosing, potentially enhancing its effectiveness while monitoring patient response closely.

What evidence suggests that tagraxofusp might be an effective treatment for leukemia maintenance post-transplant?

Research has shown that tagraxofusp, a drug targeting a protein on cancer cells, has potential in preventing cancer recurrence after stem cell transplants. Other studies have demonstrated its effectiveness in helping patients with certain blood cancers, such as blastic plasmacytoid dendritic cell neoplasm, remain cancer-free for longer periods. This indicates that the drug has effectively helped many patients stay free of cancer for extended durations. In this trial, participants will receive escalating doses of tagraxofusp to evaluate its effectiveness in maintaining leukemia remission post-transplant. Tagraxofusp has also been linked to long-term survival, with manageable side effects in some patients. Its ability to specifically target cancer cells makes it a promising option for preventing leukemia recurrence after a transplant. ^{2 6 7 8 9}

Who Is on the Research Team?

Karen Ballen

Principal Investigator

UVA

Are You a Good Fit for This Trial?

Adults aged 18-75 with CD123+ myelofibrosis, chronic myelomonocytic leukemia, or acute myeloid leukemia who've had a stem cell transplant within the last 60-120 days. They should be in remission post-transplant and have good organ function. Participants must agree to use contraception and adhere to lifestyle guidelines.

Inclusion Criteria

Patient meets the 2016 WHO diagnostic criteria for MF, is CD 123+, and has an IPSS/DIPSS/DIPSS-plus intermediate-1 with anemia (Hb < 10g/dl), splenomegaly (> 12 cm), leukocytosis (WBC > 25K) intermediate-2 or high-risk disease pre transplant, or Patient has a 2016 WHO-defined diagnosis of CMML pre transplant and is CD123+, or Patient has 2016 WHO-defined CMML-1 and CMML-2 pre transplant and is CD 123+, or Patient has CD 123+ AML in morphologic remission pre transplant, Receipt of first allogeneic stem cell transplant (related, unrelated, haploidentical or cord blood) 60-120 days prior to study registration, Patient is in morphologic remission post-HCT and at the time of study registration, Provision of signed and dated informed consent form, Stated willingness to comply with all study procedures and availability for the duration of the study, For females and males of reproductive potential: agreement to use adequate contraception for at least one month prior to screening, during study participation and for an additional one week after the end of study drug administration. Other (non-study) medications may require participants to use adequate contraception for longer, For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner. Other (non-study) medications may require participants to use adequate contraception for longer, Agreement to adhere to Lifestyle Considerations throughout study duration

I can take care of myself and am up and about more than half of my waking hours.

Patient has a life expectancy of >6 months

Exclusion Criteria

I do not have serious heart problems like uncontrolled heart failure or recent heart attack.

I have a history of cancer, but it's not one that would affect this study's results.

I do not have any severe illnesses or social situations that would stop me from following the study's requirements.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tagraxofusp starting between 60 and 120 days following HCT, with up to 9 cycles of treatment. Tag is given by IV on days 1-3 of cycles 1-4 and days 1-2 of subsequent cycles.

9 cycles (each cycle is 28 days)

Inpatient for cycle 1, outpatient for subsequent cycles with 4-hour observation post-infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment, including regular blood checks and bone marrow biopsies after cycle 4 and about 1 year after HCT.

2 years after HCT

What Are the Treatments Tested in This Trial?

Interventions

• Tagraxofusp

Trial Overview The trial is testing Tagraxofusp as a maintenance therapy after allogeneic stem cell transplant for patients with certain blood cancers. It aims to prevent cancer relapse over up to nine treatment cycles, including bone marrow biopsies after cycle four and around one year post-transplant.

How Is the Trial Designed?

Group I: Tagraxofusp (escalating doses) Experimental Treatment 1 Intervention

IV tagraxofusp on days 1-3 of cycles 1-4 and days 1-2 of additional cycles for up to 9 cycles (some participants could receive more if considered in their best interest)

Who Is Running the Clinical Trial?

Karen Ballen, MD

Lead Sponsor

Trials

1

Recruited

40+

Published Research Related to This Trial

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]

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]

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]

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]

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]

A study involving primary leukemic blasts from 34 patients with acute myeloid leukemia (AML) found that a diphtheria toxin fused to a variant interleukin-3 (DT388IL-3[K116W]) was significantly more effective at killing leukemic cells than the standard version (DT388IL-3).

The effectiveness of these fusion proteins in killing leukemic cells was directly related to the levels of interleukin-3 receptor alpha and beta expressed on the cells, suggesting that measuring these receptor levels could help identify patients who would benefit from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diphtheria toxin fused to variant human interleukin-3 induces cytotoxicity of blasts from patients with acute myeloid leukemia according to the level of interleukin-3 receptor expression. Testa, U., Riccioni, R., Biffoni, M., et al.[2021]

Diphtheria fusion proteins, specifically DT(388)IL3, show promise in treating chemotherapy-resistant acute myeloid leukemia (AML), with 36% of patient samples demonstrating significant cytotoxicity.

The effectiveness of DT(388)IL3 is correlated with the density of high-affinity IL3 receptors on leukemia cells, suggesting that targeting these receptors may enhance treatment sensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High affinity interleukin-3 receptor expression on blasts from patients with acute myelogenous leukemia correlates with cytotoxicity of a diphtheria toxin/IL-3 fusion protein. Alexander, RL., Ramage, J., Kucera, GL., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12213941/

Tagraxofusp maintenance post-hematopoietic stem cell ... Tagraxofusp maintenance post-hematopoietic stem cell transplantation provides long-term survival and manageable safety for a patient with blastic plasmacytoid ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05233618

NCT05233618 | Study of Tagraxofusp for Post-Transplant ... In this study, tagraxofusp (Tag) is given to patients with CD 123+ myelofibrosis (MF), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia ...

3. 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.

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-04826

Tagraxofusp Maintenance Therapy to Prevent Relapse in ... Maintenance therapy is given after stem cell transplant to prevent the cancer from coming back. Tagraxofusp is a drug that targets cells that have CD123 on ...

5. targetedonc.com targetedonc.com/view/long-term-bpdcn-data-show-potential-for-durable-crs-and-transplant

Long-Term BPDCN Data Show Potential for Durable CRs ... He received tagraxofusp 12 mg/kg as per package label (days 1-5 of a 21-day cycle) for frontline therapy and achieved complete response (CR) ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05716009

Study Details | NCT05716009 | Tagraxofusp-erzs, an IL-3 ... The goal of this study is to study the safety and tolerability of a novel combination of medications in relapsed or refractory AML: tagraxofusp and gemtuzumab ...

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

Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic ... In vitro interleukin-3 binding to leukemia cells predicts cytotoxicity of a diphtheria toxin/IL-3 fusion protein . Bioconjug Chem . 2000.

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

Tagraxofusp (SL-401) therapy for blastic plasmacytoid ... Tagraxofusp is comprised of recombinant human interleukin-3 (IL-3) fused to a truncated diphtheria toxin payload. It is composed of IL3 fused via a Met-His ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7448601/

Approval of tagraxofusp-erzs for blastic plasmacytoid ... In vitro interleukin-3 binding to leukemia cells predicts cytotoxicity of a diphtheria toxin/IL-3 fusion protein. Bioconjug Chem. 2000;11(4): ...