Tagraxofusp + Venetoclax + Azacitidine for Acute Myeloid Leukemia

(TRILLIUM Trial)

Recruiting at 38 trial locations

Overseen By Stemline Trials

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Stemline Therapeutics, Inc.

Must not be taking: Hypomethylating agents, Venetoclax

Disqualifiers: Prior AML therapy, CNS involvement, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This study will be divided into 2 parts (Part 1 and Part 2). Part 1 will evaluate 2 doses of tagraxofusp (9 and 12 micrograms/kilogram/day \[μg/kg/day\]), used in combination with venetoclax and azacitidine, to determine the dose for Part 2. This determined dose, in combination with venetoclax and azacitidine, will then be further evaluated in Part 2 in 2 cohorts (TP53 mutated and TP53 wild type). Both parts will be conducted in participants with previously untreated CD123+ AML who are ineligible for intensive chemotherapy.

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.

What data supports the effectiveness of the drug combination Tagraxofusp, Venetoclax, and Azacitidine for treating Acute Myeloid Leukemia?

Research shows that the combination of venetoclax and azacitidine significantly improves survival in patients with newly diagnosed acute myeloid leukemia who are not eligible for intensive chemotherapy. Additionally, venetoclax combined with azacitidine has been shown to be cost-effective in achieving remission compared to other treatments. ^{1 2 3 4 5}

Is the combination of Tagraxofusp, Venetoclax, and Azacitidine safe for humans?

The combination of Venetoclax and Azacitidine has been found to have acceptable safety in patients with acute myeloid leukemia, although dose reduction is sometimes needed due to therapy-related side effects. There is no specific safety data available for the combination including Tagraxofusp. ^{4 5 6 7 8}

What makes the drug combination of Tagraxofusp, Venetoclax, and Azacitidine unique for treating acute myeloid leukemia?

This drug combination is unique because it targets CD123-positive cells with Tagraxofusp, a fusion protein that combines a diphtheria toxin with interleukin-3, while Venetoclax and Azacitidine work together to enhance its effectiveness and overcome resistance, offering a novel approach for treating acute myeloid leukemia. ^{1 5 9 10 11}

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Azacitidine (Anti-metabolites)
• Tagraxofusp (Monoclonal Antibodies)
• Venetoclax (Other)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Findings from Research

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 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 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]

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]

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]

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]

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]

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]

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 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]

References

1. China pubmed.ncbi.nlm.nih.gov

[Efficacy of Venetoclax Plus Azacitidine in Relapsed/Refractory Acute Myeloid Leukemia Patients with FLT3-ITD Mutation]. [2023]

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

TP53 or Not TP53: That Is the Question. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. [2023]

4. United States 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. [2022]

5. China 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]. [2023]

6. China pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia. [2023]

8. United States 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. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Tagraxofusp in myeloid malignancies. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. [2022]