Tagraxofusp + Decitabine for Chronic Myelomonocytic Leukemia

Overseen By Guillermo Bravo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Investigational agents

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, up to 7 cycles

64 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and understand the side effects of two treatments, tagraxofusp (Elzonris) and decitabine, for chronic myelomonocytic leukemia, a type of blood cancer. Tagraxofusp targets and kills cancer cells, while decitabine stops cancer cells from growing and spreading. The trial includes adults with this specific leukemia who haven't responded well to other treatments. Participants should be able to manage daily activities and not have other serious health issues.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this potentially groundbreaking therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are taking hydroxyurea, you may continue it during the first cycle of the study, and possibly beyond with approval from the Principal Investigator.

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

Research shows that tagraxofusp is usually well-tolerated. In studies, patients experienced a noticeable decrease in spleen size and improvements in bone marrow health. However, like any treatment, some side effects have been reported, though specific details are not available in the sources provided.

Decitabine has proven effective and safe for patients with conditions like chronic myelomonocytic leukemia (CMML). Studies have reported high success rates and a good safety record in treating CMML. Most patients manage the treatment well, but, like other medications, it can have side effects.

Both treatments have undergone research for safety and effectiveness, providing a good level of confidence in their use. However, each person's experience can differ. Always discuss potential risks and benefits with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of tagraxofusp and decitabine for treating Chronic Myelomonocytic Leukemia (CMML) because it offers a novel approach compared to existing treatments like hydroxyurea and hypomethylating agents. Tagraxofusp is unique because it is a targeted therapy that works by delivering a cytotoxic protein to cells that express the interleukin-3 receptor, which is often found on CMML cells. This mechanism is different from traditional chemotherapy, which targets all rapidly dividing cells, not just cancerous ones. Additionally, when paired with decitabine, which helps by reactivating genes that suppress tumors, this combination could potentially enhance treatment effectiveness and improve outcomes for patients with CMML.

What evidence suggests that tagraxofusp and decitabine might be an effective treatment for chronic myelomonocytic leukemia?

Research has shown that combining tagraxofusp with decitabine may help treat chronic myelomonocytic leukemia (CMML). In this trial, participants will receive both tagraxofusp and decitabine as part of the treatment regimen. Tagraxofusp targets and kills cancer cells by attaching to a specific marker and delivering a toxic substance. Decitabine stops cancer cells from growing and multiplying. Previous studies found that tagraxofusp is generally safe, but it hasn't been very effective on its own for CMML. By combining it with decitabine, the treatment aims to better control the disease by using two different methods to attack the cancer cells. ^{6 7 8 9 10}

Who Is on the Research Team?

Guillermo M. Bravo

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with chronic myelomonocytic leukemia (CMML) who haven't tried hypomethylating agents or have no response after 6 cycles of such treatments. They should be in good heart health, have acceptable organ function, and not be pregnant. Participants must agree to use contraception and can't join if they've had recent other cancer treatments, significant heart or lung disease, active infections like HIV or hepatitis B/C, or are on certain immunosuppressants.

Inclusion Criteria

The patient or legally authorized representative has signed informed consent prior to initiation of any study-specific procedures or treatment

If a woman of childbearing potential (WOCBP), the patient has a negative serum or urine pregnancy test within 1 week prior to tagraxofusp treatment

I am either in the relapsed group or have never had HMA treatment.

Exclusion Criteria

I have or might have cancer that has spread to my brain or spinal cord.

Patient is pregnant or breastfeeding

I am currently receiving treatment for an active cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive decitabine IV over 60 minutes on days 1-5, and tagraxofusp-erzs IV over 15 minutes on days 1-3. Cycles of decitabine repeat every 28 days, and tagraxofusp-erzs repeats every 28 days for up to 7 cycles.

28 days per cycle, up to 7 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 3 months.

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Tagraxofusp-erzs

Trial Overview The trial is testing the combination of Tagraxofusp-erzs and Decitabine for treating CMML. Tagraxofusp targets cancer cells with a toxin linked to IL3 while Decitabine interferes with cell growth. The study aims to find the best dose and see how effective this combo is at controlling the disease.

How Is the Trial Designed?

Group I: Treatment (decitabine, tagraxofusp-erzs) Experimental Treatment 2 Interventions

Patients receive decitabine IV over 60 minutes on days 1-5, and tagraxofusp-erzs IV over 15 minutes on days 1-3. Cycles of decitabine repeat every 28 days in the absence of disease progression or unacceptable toxicity. Treatment with tagraxofusp-erzs repeats every 28 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

Oral azacitidine (CC-486) has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia who are in complete remission, highlighting its efficacy in this specific patient population.

The combination of decitabine and cedazuridine (ASTX727) is approved for treating adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia, particularly those with intermediate-1 or higher risk, indicating its targeted therapeutic application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. Kipp, D., H Wei, A.[2022]

Decitabine showed an overall response rate of 25% in treating chronic myelomonocytic leukemia (CMML), with 14% of patients achieving a complete response and 11% a partial response, based on a review of 31 patients across three clinical trials.

The safety profile of decitabine in CMML patients was consistent with other hematologic conditions, primarily involving myelosuppression and related infections, indicating that it may be a viable treatment option for this challenging disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML). Wijermans, PW., Rüter, B., Baer, MR., et al.[2018]

Decitabine treatment in patients with chronic myelomonocytic leukemia showed modest clearance of mutant alleles after the first cycle, but significant clearance was observed after 2 to 4 cycles, correlating with clinical responses in some patients.

The study suggests that decitabine operates through a noncytotoxic mechanism, leading to changes in the biology of cancer cells rather than directly killing them, as evidenced by the sustained clinical remissions in two patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia. Oki, Y., Jelinek, J., Shen, L., et al.[2021]

The phase 2 study found that oral cedazuridine/decitabine (100 mg/35 mg) provided similar systemic exposure and DNA demethylation compared to standard IV decitabine (20 mg/m2) in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, indicating comparable efficacy.

Clinical responses were observed in 60% of patients, with 21% achieving a complete response, while the most common serious side effects included neutropenia (46%) and thrombocytopenia (38%), highlighting the treatment's safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Garcia-Manero, G., Griffiths, EA., Steensma, DP., et al.[2021]

Decitabine is a DNA methyltransferase inhibitor with a long history of antileukemic efficacy, particularly effective in treating acute myeloid leukemia in older patients or those unable to undergo intensive therapy.

The current dosing regimen of decitabine (20 mg/m² for 5 days) has been refined to minimize nonhematologic toxicity, making it a promising option for patients who may not tolerate more aggressive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine for acute myeloid leukemia. Marks, PW.[2018]

In a study of 106 patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, decitabine showed an overall improvement rate of 35%, indicating its efficacy in treating these conditions.

The treatment was well tolerated, with a 2-year overall survival rate of 71%, although some patients experienced treatment-related adverse events and 21% developed acute myelogenous leukemia during follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine in myelodysplastic syndromes and chronic myelomonocytic leukemia: Argentinian/South Korean multi-institutional clinical experience. Iastrebner, M., Jang, JH., Nucifora, E., et al.[2019]

Decitabine maintenance therapy significantly improves overall survival (34.7 months) and relapse-free survival (30.1 months) in patients with medium- and low-risk acute myeloid leukemia compared to a control group, indicating its efficacy as a treatment option.

The therapy enhances the immune response by increasing CD3+ T cells, CD8+ T cells, and NK cells while reducing regulatory T cells, suggesting a mechanism of action that boosts the body's ability to fight cancer, with a low incidence of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effectiveness and Mechanism of Decitabine Maintenance Therapy in Patients with Medium and Low-risk Acute Myeloid Leukemia]. Dong, Y., Wang, J., Tao, QS., et al.[2022]

In a phase 2 study involving 43 patients with chronic myelomonocytic leukemia (CMML), decitabine treatment resulted in an overall response rate of 47.6%, indicating its potential efficacy in this challenging condition.

The median overall survival for patients treated with decitabine was 17 months, with responders experiencing significantly longer survival compared to non-responders, highlighting the treatment's impact on patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia. Santini, V., Allione, B., Zini, G., et al.[2019]

The fixed-dose oral combination of decitabine and cedazuridine (Inqovi®) has been approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), enhancing the oral bioavailability of decitabine through the inhibition of cytidine deaminase by cedazuridine.

Decitabine is already an established treatment for MDS and CMML, and the combination therapy has shown promise in ongoing clinical studies for other cancers like acute myeloid leukaemia (AML), glioma, and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. Dhillon, S.[2021]

The combination of oral cedazuridine and decitabine (C-DEC) has been shown to have a similar pharmacokinetic and pharmacodynamic profile to parenteral decitabine, making it a promising alternative for treating higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).

Phase 2 and phase 3 clinical trials confirmed the bioequivalence of C-DEC to parenteral decitabine, leading to FDA approval for its use in intermediate/high-risk MDS and CMML, highlighting its efficacy and safety as an oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies. Patel, AA., Cahill, K., Saygin, C., et al.[2023]

Citations

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Tagraxofusp, a CD123-targeted therapy, for chronic ... Tagraxofusp demonstrated a manageable safety profile with limited clinical efficacy in CMML. This trial was registered at www.ClinicalTrials.gov as #NCT02268253 ...

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Study Details | NCT02268253 | Tagraxofusp (SL-401) in ... This multicenter, multi-arm trial evaluated the safety and efficacy of tagraxofusp, a cell division cycle protein 123 homolog-targeted therapy, ...

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Phase I/II Study of Tagraxofusp in Combination ... - MedPath This phase I/II trial studies the side effects, best dose, and effect of tagraxofusp and decitabine in treating patients with chronic myelomonocytic leukemia.

4. stemline.com stemline.com/wp-content/uploads/2023/01/Patnaik-ASH-2021-oral-slides-CMML-_FINAL.pdf

Updated Results of an Ongoing Phase 1/2 Trial Tagraxofusp in Patients with Chronic Myelomonocytic. Leukemia (CMML): Updated ... ▻ Poor clinical outcomes in CMML result from bone marrow failure, high risk of ...

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NCT05038592 | Phase I/II Study of Tagraxofusp in ... This phase I/II trial studies the side effects, best dose, and effect of tagraxofusp and decitabine in treating patients with chronic myelomonocytic leukemia.

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Efficacy and safety of oral decitabine/cedazuridine in the ... This analysis described the use of decitabine/cedazuridine in CMML from consecutive, prospective, randomised trials and illustrated a median survival of nearly ...

7. ashpublications.org ashpublications.org/blood/article/116/21/4032/68169/Decitabine-Is-Effective-and-Safe-In-Patients-with

Decitabine Is Effective and Safe In Patients with Chronic ... Decitabine Is Effective and Safe In Patients with Chronic Myelomonocytic Leukemia Available ... CMML treated on two decitabine studies.

8. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118440955

Decitabine Induces High Response Rates in Patients with ... Conclusions Decitabine is active and safe in CMML. Future studies may combine decitabine with histone deacetylase inhibitors, chemotherapy (eg cytarabine, ...

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An update on the safety and efficacy of decitabine ... This review presents the current data available on the clinical efficacy and safety profile for decitabine as a treatment for MDS.

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Oral Decitabine-Cedazuridine Is a Game Changer for ... Long-term data from the phase 3 ASCERTAIN trial (NCT03306264), recently published in The Lancet Haematology, confirm the safety and efficacy of ...