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

Trial Summary

What is the purpose of this trial?

In this study, tagraxofusp (Tag) is given to patients with CD 123+ myelofibrosis (MF), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) after allogeneic stem cell transplant (HCT) to help prevent relapse. Patients will receive up to about 9 cycles of treatment with Tag and have a bone marrow biopsy after cycle 4 and about 1 year after HCT.

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.

What data supports the effectiveness of the drug Tagraxofusp for leukemia maintenance post-transplant?

Tagraxofusp, a drug that combines diphtheria toxin with interleukin-3, has shown promising results in treating certain blood cancers by targeting specific receptors on cancer cells. Studies have demonstrated its ability to kill leukemia cells and prolong survival in animal models, suggesting potential effectiveness in similar human conditions. ^{1 2 3 4 5}

What safety data exists for Tagraxofusp in humans?

Tagraxofusp has been shown to have a manageable safety profile in humans, with common side effects including mild liver enzyme changes, 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 5 6 7}

How is the drug Tagraxofusp unique for leukemia maintenance post-transplant?

Tagraxofusp is unique because it combines a diphtheria toxin with interleukin-3, specifically targeting leukemia cells that overexpress the interleukin-3 receptor, which is not a common approach in standard leukemia treatments. This targeted mechanism allows it to kill leukemia cells while sparing normal cells, offering a novel strategy for patients who may not respond well to traditional chemotherapy. ^{1 2 3 5 8}

Research Team

Karen Ballen

Principal Investigator

UVA

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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 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 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]

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. Switzerland pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

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

3. United States 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. [2021]

4. England 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. [2019]

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. England pubmed.ncbi.nlm.nih.gov

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

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

Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia. [2019]

8. 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]