SL-401 + Azacitidine/Venetoclax for AML and MDS

Recruiting at 2 trial locations

Overseen By Veronica Zehnder

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Venetoclax, Strong CYP3A inducers

Disqualifiers: APL, Active CNS involvement, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 cycles (approximately 6 months)

72 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of drugs—SL-401 (Tagraxofusp or Elzonris), Azacitidine, and Venetoclax—to determine their effectiveness in treating certain blood cancers. It focuses on conditions like acute myeloid leukemia (AML), which affects blood and bone marrow, as well as high-risk myelodysplastic syndrome (MDS) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Participants will receive various combinations of these drugs to identify the most effective treatment plan. Individuals with AML or MDS who have specific cell markers and have either relapsed or are unsuitable for intensive chemotherapy might be a good fit. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot have taken venetoclax within 2 months before starting the trial. Also, you should not be on strong CYP3A inducers within 7 days of starting the study treatment.

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

Research has shown that using SL-401 with azacitidine, or with azacitidine and venetoclax, is generally safe. Previous studies found these treatments are usually well-tolerated, with no additional cases of capillary leak syndrome (where fluid leaks from small blood vessels) or infections. This indicates the combination does not cause more serious side effects than expected. Researchers conducted these studies to assess the safety of these drugs when used together, closely monitoring patient reactions.

For those considering joining a trial, this information may reassure about the safety of these treatments. However, each person's experience can differ, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine a novel biologic, SL-401, with existing chemotherapy agents, offering a fresh approach to tackling acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Unlike traditional treatments that primarily target rapidly dividing cells, SL-401 specifically targets a protein called CD123 found on the surface of leukemia cells, potentially reducing harm to healthy cells. Additionally, the combination of SL-401 with Azacitidine and Venetoclax could enhance the overall effectiveness by attacking the cancer cells through multiple mechanisms, which might improve patient outcomes compared to existing standard therapies.

What evidence suggests that this trial's treatments could be effective for AML and MDS?

This trial will evaluate two treatment combinations for AML (acute myeloid leukemia) and high-risk MDS (myelodysplastic syndrome). One arm will test the combination of SL-401 with azacitidine. Studies have shown that this combination can be more effective than using either drug alone, as it affects certain proteins in the blood and bone marrow, potentially helping to fight these diseases. Another arm will test the addition of venetoclax to SL-401 and azacitidine. Research suggests that adding venetoclax is safe, with manageable side effects, and enhances the effects of each drug against cancer cells. Overall, early evidence suggests these treatments might offer a promising option for patients with these conditions. ^{1 2 3 4 6}

Who Is on the Research Team?

Andrew Lane, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with confirmed diagnoses of AML, high-risk MDS, or BPDCN who have adequate organ function and can consent to the study. They must not be pregnant, breastfeeding, have active CNS involvement by their disease, known HIV/Hepatitis B/C infections, other advanced malignancies needing treatment or gastrointestinal conditions affecting medication absorption.

Inclusion Criteria

I am 18 or older with BPDCN that has come back or didn't respond to treatment, excluding hydroxyurea.

Ability to understand and the willingness to sign a written informed consent document

Able to adhere to study visit schedule and other protocol requirements including follow-up for survival assessment

Exclusion Criteria

I have been diagnosed with acute promyelocytic leukemia.

I haven't had cancer treatment in the last 14 days, except for intrathecal chemotherapy or hydroxyurea.

I had a stem cell transplant less than 2 months ago or have ongoing graft versus host disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive SL-401 in combination with azacitidine or azacitidine/venetoclax on a 28-day cycle

6 cycles (approximately 6 months)

Monthly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Extension

Participants may continue to receive treatment if beneficial

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• SL-401
• Venetoclax

Trial Overview The trial is testing SL-401 in combination with Azacitidine alone or with Venetoclax for treating AML, high-risk MDS, and BPDCN. It aims to evaluate the effectiveness and safety of these drug combinations in different patient cohorts based on their specific conditions.

How Is the Trial Designed?

Group I: SL-401+ Azacitidine + Venetoclax Experimental Treatment 3 Interventions

SL-401 will be administered every 4 weeks, on a 28 day cycle; SL-401 will be given intravenously; Azacitidine will be administered every 4 weeks, on a 28 day cycle; Azacitidine will be given intravenously or subcutaneously; Venetoclax will be administered for 21 days on a 28 day cycle; Venetoclax will be taken orally

Group II: SL-401+ Azacitidine Experimental Treatment 2 Interventions

SL-401 will be administered every 4 weeks, on a 28 day cycle; SL-401 will be given intravenously; Azacitidine will be administered every 4 weeks, on a 28 day cycle; Azacitidine will be given intravenously or subcutaneously

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?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Stemline Therapeutics, Inc.

Collaborator

Trials

24

Recruited

6,500+

Stemline Therapeutics, Inc.

Industry Sponsor

Trials

24

Recruited

6,500+

Published Research Related to This Trial

In a study of 57 elderly patients (average age 69.9 years) with acute myeloid leukemia, the combination of venetoclax and azacitidine (VEN + AZA) showed a high overall response rate of 87.5% and a complete remission (CR) rate of 68.8%, indicating strong efficacy in this population.

The treatment was associated with a median overall survival (OS) of 11.5 months, and achieving minimal residual disease (MRD) negativity (<0.1%) was more common with VEN + AZA compared to traditional chemotherapy, although older patients (≥75 years) and those with higher ECOG scores faced more challenges in achieving MRD negativity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. Yu, H., Wang, C., Lei, Y., 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]

The combination of venetoclax (Ven) and azacitidine (AZA) shows a high efficacy in treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with an overall complete response rate of 57.9% across 19 studies involving 1615 patients.

This treatment is particularly effective for newly diagnosed AML patients, achieving a complete response rate of 67.5%, although it is less effective for those with relapsed or refractory AML, which had a response rate of only 30%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis. Du, Y., Li, C., Yan, J.[2023]

In the HiDDAV study involving 42 newly diagnosed AML patients, higher doses of venetoclax (600 mg daily) were found to be tolerable but did not show significant clinical improvement compared to the standard 400 mg dose.

The study revealed that using minimal residual disease (MRD) status to guide the discontinuation of azacitidine did not lead to better outcomes in terms of duration of response or overall survival, suggesting that alternative strategies are needed to optimize treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia. Gutman, JA., Winters, A., Kent, A., et al.[2023]

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., 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 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., 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 phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03113643

NCT03113643 | SL-401 in Combination With Azacitidine or ... This study will also look at how the SL-401, in combination with azacitidine or azacitidine/venetoclax, affects certain proteins in your blood and bone marrow.

2. sciencedirect.com sciencedirect.com/science/article/pii/S000649712104297X

Safety and Efficacy of Combining Tagraxofusp (SL-401) ... TAG resistance was reversible by the hypomethylating agent azacitidine (AZA), and TAG plus AZA was more effective than either alone in xenograft ...

3. ashpublications.org ashpublications.org/bloodadvances/article/8/3/591/506508/Phase-1b-trial-of-tagraxofusp-in-combination-with

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.TAG-AZA-VEN has e.

4. 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.

5. clin.larvol.com clin.larvol.com/trial-detail/NCT03113643

SL-401 in Combination With Azacitidine or ... Impact Score 3SL-401 in Combination With Azacitidine or Azacitidine/Venetoclax in Acute Myeloid Leukemia (AML), High-Risk Myelodysplastic Syndrome (MDS) or ...

6. researchgate.net researchgate.net/publication/356501837_Safety_and_Efficacy_of_Combining_Tagraxofusp_SL-401_with_Azacitidine_or_Azacitidine_and_Venetoclax_in_a_Phase_1b_Study_for_CD123_Positive_AML_MDS_or_BPDCN

Safety and Efficacy of Combining Tagraxofusp (SL-401) ... TAG resistance was reversible by the hypomethylating agent azacitidine (AZA), and TAG plus AZA was more effective than either alone in xenograft ...