Tagraxofusp + Venetoclax + Azacitidine for Acute Myeloid Leukemia

(TRILLIUM Trial)

Recruiting at 48 trial locations

Overseen By Stemline Trials

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Stemline Therapeutics, Inc.

Must not be taking: Hypomethylating agents, Venetoclax

Disqualifiers: Prior AML therapy, CNS involvement, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 10

76 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—tagraxofusp, venetoclax, and azacitidine—to evaluate their effectiveness in treating acute myeloid leukemia (AML), a type of blood cancer. The first part of the trial determines the optimal dose of tagraxofusp, a diphtheria toxin-IL-3 fusion protein targeting the IL-3 receptor. This dose will then be used in the second part to assess its effects on different genetic types of AML. Individuals who have not yet received treatment for AML and cannot undergo intensive chemotherapy might be suitable candidates for this study. This trial could provide a new option for those with AML marked by CD123+. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that combining the drugs tagraxofusp, venetoclax, and azacitidine is safe for patients with acute myeloid leukemia (AML). In studies, even patients with high-risk conditions like TP53 mutations tolerated this treatment well. Importantly, there was no increased risk of serious issues such as capillary leak syndrome or infections. These findings support further research into using this treatment for AML patients who cannot undergo intensive chemotherapy. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Tagraxofusp, Venetoclax, and Azacitidine for treating Acute Myeloid Leukemia (AML) because it introduces a unique approach compared to standard treatments like chemotherapy. Unlike traditional options, Tagraxofusp is a targeted therapy that specifically attacks cancer cells by recognizing a protein called CD123, which is commonly found on leukemia cells. This targeted action could potentially reduce damage to healthy cells, leading to fewer side effects. Additionally, combining Tagraxofusp with Venetoclax and Azacitidine might enhance the overall effectiveness by attacking the cancer cells from multiple angles, possibly improving outcomes for patients with AML.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

This trial will evaluate the combination of three drugs—tagraxofusp, venetoclax, and azacitidine—for treating acute myeloid leukemia (AML). Research has shown that this combination may be particularly effective for high-risk AML, including cases with TP53 mutations. In earlier studies, this treatment was safe and showed positive results, making it a potential option for patients who cannot undergo intensive chemotherapy. Tagraxofusp targets a protein called CD123, often found on leukemia cells, helping to destroy them. Venetoclax and azacitidine work together to further weaken the cancer cells, possibly boosting the treatment's overall effect. These findings support further research into using this drug combination for AML. Participants in this trial will receive different dosages of tagraxofusp in combination with venetoclax and azacitidine, depending on their TP53 mutation status. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with a type of blood cancer called CD123+ Acute Myeloid Leukemia (AML) who haven't been treated yet and can't handle strong chemotherapy. The specific criteria to join or reasons you can't participate aren’t listed here.

Inclusion Criteria

Histologically confirmed newly diagnosed AML with bone marrow blast count ≥20%.

Participant has any level of CD123 expression on blasts determined centrally by flow cytometry.

Eastern Cooperative Oncology Group (ECOG) Score of 2 or 3.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Evaluation of 2 doses of tagraxofusp (9 and 12 μg/kg/day) in combination with venetoclax and azacitidine to determine the dose for Part 2

16 weeks

4 cycles of 28 days each

Treatment Part 2

Further evaluation of the selected dose of tagraxofusp in combination with venetoclax and azacitidine in 2 cohorts (TP53 mutated and TP53 wild type)

24 weeks

6 cycles of 28 days each

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 6 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Tagraxofusp
• Venetoclax

Trial Overview The study tests different doses of Tagraxofusp combined with Venetoclax and Azacitidine in two parts. Part 1 finds the right dose, which is then used in Part 2 to see how well it works for treating AML without intense chemo.

How Is the Trial Designed?

Group I: Part 2 - Tagraxofusp (Selected Dose) and TP53 Wild Type Experimental Treatment 3 Interventions

Participants (TP53 wild type) will receive tagraxofusp in combination with venetoclax and azacitidine.

Group II: Part 2 - Tagraxofusp (Selected Dose) and TP53 Mutated Experimental Treatment 3 Interventions

Participants (TP53 mutated) will receive tagraxofusp in combination with venetoclax and azacitidine.

Group III: Part 1 - Tagraxofusp (9 μg/kg/day) Experimental Treatment 3 Interventions

Participants will receive tagraxofusp in combination with venetoclax and azacitidine.

Group IV: Part 1 - Tagraxofusp (12 μg/kg/day) Experimental Treatment 3 Interventions

Participants will receive tagraxofusp in combination with venetoclax and azacitidine.

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Stemline Therapeutics, Inc.

Lead Sponsor

Trials

24

Recruited

6,500+

Stemline Therapeutics, Inc.

Lead Sponsor

Trials

24

Recruited

6,500+

Published Research Related to This Trial

A lower dosage of Venetoclax (100 mg) combined with Azacitidine showed favorable outcomes in newly diagnosed acute myeloid leukemia (AML) patients, with a median overall survival of 17 months and an overall response rate of 69.4% based on a study of 36 patients.

The study suggests that even with dose reductions of Venetoclax, the combination therapy remains effective, indicating a potential strategy to manage therapy-related toxicity while still achieving significant treatment responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia. Cui, J., Chen, X., Li, C., et al.[2023]

In a study of 50 adults with acute myeloid leukemia (AML) in Mexico and Peru, venetoclax-based therapy showed a high complete response rate of 78.6% in newly diagnosed patients and 45.5% in those with relapsed/refractory disease, indicating its efficacy in treating AML.

The median overall survival was 9.6 months for newly diagnosed patients and 8 months for relapsed/refractory patients, suggesting that venetoclax is a viable treatment option even in real-world settings, despite common hematologic toxicities and dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. Gómez-De León, A., Demichelis-Gómez, R., Pinedo-Rodríguez, A., et al.[2022]

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]

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[2023]

In a study of 16 patients with FLT3-ITD mutated relapsed/refractory acute myeloid leukemia (AML), the combination of venetoclax (VEN) and azacitidine (AZA) showed some efficacy, with 14.3% of FLT3-ITDmut patients achieving complete remission, similar to the 22.2% in the FLT3-ITD wild-type group.

Patients with FLT3-ITD mutations had a significantly shorter median overall survival (130 days) compared to those without the mutation (300 days), suggesting that additional treatments, like transplantation, may be necessary for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of Venetoclax Plus Azacitidine in Relapsed/Refractory Acute Myeloid Leukemia Patients with FLT3-ITD Mutation]. Weng, GY., You, WW., Liu, HX., et al.[2023]

In a study of 6 children with refractory or relapsed acute myeloid leukemia (AML), the combination of venetoclax, azacitidine, and cladribine (VAC regimen) resulted in significant treatment responses, with 4 achieving complete remission and 1 showing partial remission.

Despite severe side effects like grade IV neutropenia and thrombocytopenia, there were no treatment-related deaths or infections, indicating that the VAC regimen is both effective and safe for this vulnerable patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. DU, WW., Liu, SX., Wang, Y., et al.[2023]

Outpatient induction therapy using low-dose venetoclax combined with itraconazole and azacitidine is feasible and safe for newly diagnosed acute myeloid leukemia (ND-AML) patients, with 77.7% of participants completing the first treatment cycle as outpatients.

The treatment showed promising efficacy, with a composite complete response rate of 53.9% after the first cycle and 85.7% after the second cycle, indicating that this regimen could be a viable option for patients eligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. De la Garza-Salazar, F., Colunga-Pedraza, PR., Gómez-Almaguer, D., et al.[2023]

In a study of 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

Venetoclax combined with azacitidine or low-dose cytarabine (LDAC) is associated with significantly lower costs per patient achieving complete remission (CR) or complete remission with incomplete blood count recovery (CRi) compared to other treatments for newly diagnosed acute myeloid leukemia (AML) patients who cannot undergo intensive chemotherapy.

The estimated costs per patient achieving CR + CRi were $473,960 for venetoclax + azacitidine and $428,071 for venetoclax + LDAC, which are substantially lower than the costs for azacitidine ($1,197,438) and other therapies, indicating a more cost-effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Costs per patient achieving remission with venetoclax-based combinations in newly diagnosed patients with acute myeloid leukemia ineligible for intensive induction chemotherapy. Choi, M., Song, J., Bui, CN., et al.[2022]

ASP1235, an antibody drug conjugate targeting FLT3, shows promising anti-tumor effects when combined with venetoclax and azacitidine in a preclinical model of acute myeloid leukemia (AML), particularly in THP-1 cells.

The combination treatment demonstrated superior efficacy compared to monotherapy and did not result in significant body weight loss, suggesting a favorable safety profile for this triple therapy in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-tumor effect of antibody drug conjugate ASP1235 targeting Fms-like tyrosine kinase 3 with venetoclax plus azacitidine in an acute myeloid leukemia xenograft mouse model. Tsuzuki, H., Kawase, T., Nakazawa, T., et al.[2023]

Citations

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Phase 1b trial of tagraxofusp in combination with azacitidine ... TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations.

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Tagraxofusp-erzs, Azacitidine and Venetoclax for the ... Giving tagraxofusp-erzs with azacitidine and venetoclax may work better in treating patients with acute myeloid leukemia or myelodysplastic syndrome compared to ...

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Paper: Tagraxofusp in Combination with Azacitidine and ... 4277 Tagraxofusp in Combination with Azacitidine and Venetoclax in Newly Diagnosed CD123+ Acute Myeloid Leukemia, Expansion Cohort of a Phase 1b ...

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Comprehensive view on chemotherapy-free management ... Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia. Blood Adv. 2024;8:591 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03113643

NCT03113643 | SL-401 in Combination With Azacitidine or ... The goal of this research study is to try and determine the safest, highest dose of study drug, SL-401, in combination with azacitidine or azacitidine/ ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10837492/

Phase 1b trial of tagraxofusp in combination with azacitidine ... Administration of tagraxofusp, azacitidine, and venetoclax is feasible without evidence of increased capillary leak syndrome or infection.

8. uclahealth.org uclahealth.org/clinical-trials/study-tagraxofusp-combination-with-venetoclax-and

A Study of Tagraxofusp in Combination With Venetoclax ... A study of tagraxofusp in combination with venetoclax and azacitidine in adults with untreated CD123+ acute myeloid leukemia who cannot undergo intensive ...