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

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects, best dose, and effect of tagraxofusp and decitabine in treating patients with chronic myelomonocytic leukemia. Tagraxofusp consists of human interleukin 3 (IL3) linked to a toxic agent called DT388. IL3 attaches to IL3 receptor positive cancer cells in a targeted way and delivers DT388 to kill them. Chemotherapy drugs, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving tagraxofusp and decitabine may help to control the disease in patients with chronic myelomonocytic leukemia.

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.

What data supports the effectiveness of the drug Tagraxofusp + Decitabine for Chronic Myelomonocytic Leukemia?

Research shows that Decitabine, a part of the treatment, has been effective in treating Chronic Myelomonocytic Leukemia (CMML) with an overall response rate of 47.6% in a study, and it is approved for use in CMML. Additionally, Decitabine combined with Cedazuridine has been approved for CMML, indicating its effectiveness in this condition. ^{1 2 3 4 5}

What safety data exists for Tagraxofusp + Decitabine treatment in humans?

Decitabine, used in combination with cedazuridine, has been studied for safety in treating conditions like myelodysplastic syndromes and chronic myelomonocytic leukemia. Common side effects include low blood cell counts, such as neutropenia (low white blood cells), thrombocytopenia (low platelets), and anemia (low red blood cells). These side effects are generally manageable, and the treatment is considered well-tolerated in patients. ^{3 5 6 7 8}

What makes the drug Tagraxofusp + Decitabine unique for treating chronic myelomonocytic leukemia?

The combination of Tagraxofusp and Decitabine is unique because it combines a targeted therapy (Tagraxofusp) with a hypomethylating agent (Decitabine), potentially offering a novel approach for chronic myelomonocytic leukemia, which lacks effective treatments. Additionally, Decitabine's oral formulation with cedazuridine improves its bioavailability, making it more convenient compared to traditional intravenous administration. ^{1 3 5 9 10}

Research Team

Guillermo M. Bravo

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML). [2018]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. [2021]

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

Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia. [2021]

5. England pubmed.ncbi.nlm.nih.gov

A phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia. [2019]

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

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. [2021]

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

Decitabine for acute myeloid leukemia. [2018]

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

Decitabine in myelodysplastic syndromes and chronic myelomonocytic leukemia: Argentinian/South Korean multi-institutional clinical experience. [2019]

9. China pubmed.ncbi.nlm.nih.gov

[Effectiveness and Mechanism of Decitabine Maintenance Therapy in Patients with Medium and Low-risk Acute Myeloid Leukemia]. [2022]

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

Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies. [2023]