Tagraxofusp + Azacitidine for AML and MDS

Overseen By Hoda Pourhassan, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Disqualifiers: Active malignancy, Cardiovascular disease, Pulmonary disease, CNS disease, others

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 24 weeks

43 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs, tagraxofusp and azacitidine, to determine if they can safely and effectively prevent acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) from returning after a donor stem cell transplant. Tagraxofusp, a diphtheria toxin-IL-3 fusion protein, targets cancer cells with the CD123 marker found on some cancer cells' surfaces, while azacitidine aids in producing healthy blood cells. Patients who have undergone a donor stem cell transplant for CD123 positive AML or MDS and are currently in remission may be suitable for this trial. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this new combination therapy.

Do I have to stop taking my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that you should not have uncontrolled illnesses or be on certain investigational agents recently. It's best to discuss your specific medications with the study team.

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

Research has shown that the combination of tagraxofusp and azacitidine is generally well-tolerated by patients. Studies have found that this treatment does not increase the risk of capillary leak syndrome, where fluid leaks from small blood vessels, or infections—common concerns with similar treatments. Although the study continues to collect safety information, early results are promising regarding patient tolerance. Patients did not experience unexpected or severe side effects, suggesting it could be a safe option for ongoing treatment of certain blood cancers like AML (acute myeloid leukemia) and MDS (myelodysplastic syndrome). ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of tagraxofusp and azacitidine for treating acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) because it offers a novel approach compared to standard treatments like chemotherapy and hypomethylating agents. Tagraxofusp is unique as it targets CD123, a protein often overexpressed in these cancer cells, potentially leading to more precise cancer cell destruction. Additionally, this treatment regimen includes azacitidine, which is known to modify genes to stop cancer cell growth. Together, these drugs may work synergistically to enhance effectiveness, offering hope for better outcomes in these challenging conditions.

What evidence suggests that tagraxofusp and azacitidine might be an effective treatment for AML and MDS?

This trial will evaluate the combination of tagraxofusp and azacitidine for treating certain blood cancers, such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Studies have shown that tagraxofusp targets cancer cells with a specific marker called CD123, aiding in the destruction of these cells and preventing cancer recurrence. Azacitidine supports the growth of normal blood cells while eliminating abnormal ones. Past studies found this combination more effective than using either drug alone. Additionally, the combination did not increase the risk of serious side effects, such as capillary leak syndrome, where fluid leaks from small blood vessels. ^{2 3 4 6 7}

Who Is on the Research Team?

Hoda Z Pourhassan, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with CD123 positive acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who have undergone a donor hematopoietic cell transplant. The study aims to find out if maintenance therapy with Tagraxofusp and Azacitidine can prevent cancer from returning.

Inclusion Criteria

STUDY MAINTENANCE TREATMENT: ANC ≥ 1.5 (within 7 days of day 1 of the cycle 1)

My kidney function, measured by creatinine clearance, is adequate.

I don't have any health issues that would make treatment too risky.

Exclusion Criteria

Any other condition including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness, that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures

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

I do not have active hepatitis B, C, or HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tagraxofusp intravenously over 15 minutes once daily on days 1-3 and azacitidine intravenously over 10-40 minutes once daily on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles.

24 weeks

6 cycles, each with multiple visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then annually for up to 2 years.

2 years

Annual visits

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Tagraxofusp

Trial Overview The trial is testing the combination of two drugs, Tagraxofusp and Azacitidine, as post-transplant maintenance therapy. It's in phase Ib to determine safety, side effects, optimal dosages, and effectiveness against AML/MDS.

How Is the Trial Designed?

Group I: Treatment (tagraxofusp, azacitidine) Experimental Treatment 6 Interventions

Patients receive tagraxofusp IV over 15 minutes QD on days 1-3 and azacitidine IV over 10-40 minutes QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and bone marrow aspiration and biopsy on study.

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?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The ROMAZA trial established that the maximum tolerated dose of the combination therapy of romidepsin (ROM) and azacitidine (AZA) for treating acute myeloid leukaemia (AML) is ROM 12 mg/m2 on Days 8 and 15, along with AZA 75 mg/m2 for a 7/28 day cycle.

Out of 38 patients treated at this maximum tolerated dose, 23.7% achieved a response by Cycle 6, with 7 patients reaching complete remission and 2 achieving partial response, indicating the potential efficacy of this combination therapy in AML patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination romidepsin and azacitidine therapy is well tolerated and clinically active in adults with high-risk acute myeloid leukaemia ineligible for intensive chemotherapy. Loke, J., Metzner, M., Boucher, R., et al.[2022]

In a study of 38 acute myeloid leukemia (AML) patients treated with azacitidine, the median overall survival was approximately 10 months for both newly diagnosed and relapsed patients, indicating its efficacy as a treatment option for those unfit for intensive chemotherapy.

The treatment showed a 29% positive effect on reducing transfusion dependency, which was linked to better survival outcomes, highlighting the potential benefits of azacitidine in managing symptoms and improving quality of life for AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Azacitidine in De Novo and Relapsed Acute Myeloid Leukemia: A Retrospective Comparative Study. Gemuenden, C., Benz, R., Senn, O., et al.[2015]

In a phase 1b study involving 56 adults with CD123-positive acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), the combination of Tagraxofusp (TAG) with azacitidine (AZA) and the BCL-2 inhibitor venetoclax (VEN) showed promising efficacy, achieving a response rate of 69% in an expansion cohort of 26 patients, including a 39% complete remission rate.

The treatment was well-tolerated, with no increased toxicity observed from the combination therapy, and median overall survival was reported at 14 months, indicating that TAG-AZA-VEN is a safe and effective option for high-risk AML patients, including those with TP53 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia. Lane, AA., Garcia, JS., Raulston, EG., et al.[2023]

Azacitidine has been shown to significantly prolong survival in higher-risk patients with myelodysplastic syndromes (MDS), marking a shift in the treatment approach for these disorders since its FDA approval in 2004.

The drug maintains a relatively safe toxicity profile, making it suitable for older patients, and is being explored in combination with other therapies to enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine in the management of patients with myelodysplastic syndromes. Khan, C., Pathe, N., Fazal, S., et al.[2021]

Azacitidine significantly improves response rates and overall survival in patients with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with a median survival increase of 9.4 months compared to conventional care in higher-risk patients.

The treatment is generally well tolerated, with peripheral cytopenias being the most common side effect, along with gastrointestinal issues and injection-site reactions, making it a viable option for elderly patients as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2022]

A phase 3 clinical trial and subsequent analysis of real-world data confirmed that azacitidine significantly improves median overall survival (OS) for patients with acute myeloid leukaemia (AML) with >30% bone marrow blasts and white blood cell counts ≤15 G/L, showing comparable results between trial participants and routine clinical practice.

The pooled analysis of 309 patients demonstrated a median OS of 10.3 months and a one-year survival rate of 45.8%, indicating that azacitidine is an effective front-line treatment for AML patients beyond those who meet strict clinical trial criteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine for Front-Line Therapy of Patients with AML: Reproducible Efficacy Established by Direct Comparison of International Phase 3 Trial Data with Registry Data from the Austrian Azacitidine Registry of the AGMT Study Group. Pleyer, L., Döhner, H., Dombret, H., et al.[2018]

In a study of 687 patients with higher-risk myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML) treated with 5-azacytidine (5-AZA), factors such as the revised International Prognostic Scoring System (IPSS-R), Eastern Cooperative Oncology Group Performance Status (ECOG PS), and high baseline serum ferritin levels were found to independently predict response to treatment and overall survival.

The study developed new modified risk classification systems (H-PSS and H-PSS-R) that better predict overall survival and leukemia-free survival in patients treated with 5-AZA, demonstrating improved predictive power compared to previous models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum ferritin and ECOG performance status predict the response and improve the prognostic value of IPSS or IPSS-R in patients with high-risk myelodysplastic syndromes and oligoblastic acute myeloid leukemia treated with 5-azacytidine: a retrospective analysis of the Hellenic national registry of myelodysplastic and hypoplastic syndromes. Papageorgiou, SG., Kotsianidis, I., Bouchla, A., et al.[2022]

Azacitidine is an effective and well-tolerated treatment for patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients who are ineligible for stem cell transplants, as demonstrated in pivotal phase 3 trials.

It is the only approved hypomethylating agent that has been shown to prolong overall survival compared to conventional care, making it the recommended first-line treatment for most patients with higher-risk MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. Scott, LJ.[2022]

In a real-life study of 49 patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), azacitidine demonstrated a clinically acceptable safety profile, with 67.3% of patients experiencing treatment-related adverse events.

Efficacy results showed that 41.4% of MDS and CMML patients achieved a complete or partial response, and 43.8% of transfusion-dependent patients became transfusion-independent, with a median overall survival of 490 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. Beguin, Y., Selleslag, D., Meers, S., et al.[2015]

The Vidaza Access Program in Belgium successfully facilitated access to azacitidine treatment for 175 patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) by streamlining the approval process for patient dossiers.

Out of the 175 patient dossiers submitted, 163 were approved by Celgene, demonstrating the program's effectiveness in ensuring timely treatment initiation without financial risk to hospitals, which is crucial for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. Meers, S., Selleslag, D., Potier, H., et al.[2018]

In a study of 38 higher risk MDS patients undergoing azacitidine (AZA) therapy, nearly half of the detected somatic mutations remained stable, while others showed significant changes, indicating that mutation dynamics can influence treatment response and overall survival.

Patients who experienced a marked decrease in their mutation burden during AZA treatment had better clinical responses, suggesting that monitoring mutation dynamics could be a valuable tool for predicting treatment outcomes in MDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Somatic mutation dynamics in MDS patients treated with azacitidine indicate clonal selection in patients-responders. Polgarova, K., Vargova, K., Kulvait, V., et al.[2019]

In a study of 149 patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), azacitidine treatment resulted in a median progression-free survival (PFS) of 10.9 months and an overall survival (OS) of 14.1 months, demonstrating its effectiveness in a real-world clinical setting.

The safety profile of azacitidine was consistent with previous clinical trials, and factors such as Eastern Cooperative Oncology Group (ECOG) performance status and red blood cell transfusion prior to treatment were identified as predictive factors for better PFS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Wehmeyer, J., Zaiss, M., Losem, C., et al.[2019]

Azacitidine was approved by the FDA for treating all subtypes of myelodysplastic syndrome (MDS) based on a randomized controlled trial showing a 16% overall response rate, with sustained responses lasting up to 17 months.

The treatment demonstrated a favorable safety profile, with no deaths attributed to azacitidine, although common side effects included gastrointestinal issues and hematologic complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Kaminskas, E., Farrell, AT., Wang, YC., et al.[2013]

Citations

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

NCT03113643 | SL-401 in Combination With Azacitidine or ... This research study is studying a drug as a possible treatment for diagnosis of AML, BPDCN and high-risk MDS.

2. 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.

3. 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.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06498973

Study Details | NCT06498973 | Tagraxofusp and ... This phase Ib trial tests the safety, side effects, best dose and effectiveness of tagraxofusp in combination with azacitidine as maintenance therapy

5. 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 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06498973

Tagraxofusp and Azacitidine for Maintenance Treatment in ... This phase Ib trial tests the safety, side effects, best dose and effectiveness of tagraxofusp in combination with azacitidine as maintenance therapy in ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS6582

Tagraxofusp and low-intensity chemotherapy for the ... Tagraxofusp (TAG), a CD-123 targeted therapy, selectively induces apoptosis in CD123-expressing cells by irreversibly inhibiting protein ...