ASTX727 + Dasatinib for Chronic Myeloid Leukemia

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Tyrosine kinase inhibitors

Disqualifiers: Heart disease, Psychiatric disorders, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 30

Duration: 3 years

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of ASTX727 and dasatinib in treating patients with newly diagnosed Philadelphia chromosome or BCR-ABL positive chronic myeloid leukemia in chronic phase. Philadelphia chromosome positive and BCR-ABL positive are types of genetic mutations (changes). Chemotherapy drugs, such as ASTX727, 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. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. ASTX727 and dasatinib may help to control Philadelphia chromosome-positive chronic myeloid leukemia or BCR-ABL positive chronic myeloid leukemia in chronic phase.

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 mentions that participants should have received minimal prior therapy for chronic myeloid leukemia, defined as less than 1 month of certain medications. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination ASTX727 and Dasatinib for treating chronic myeloid leukemia?

Research shows that combining dasatinib with decitabine, a component of ASTX727, is safe and effective for advanced chronic myeloid leukemia, with nearly half of the patients achieving significant blood and genetic responses, and improved survival rates. ^{1 2 3 4 5}

Is the combination of ASTX727 and Dasatinib safe for treating chronic myeloid leukemia?

The combination of dasatinib and decitabine (part of ASTX727) has been studied in patients with advanced chronic myeloid leukemia, showing it to be generally safe, though some patients experienced serious side effects like blood-related issues. Dasatinib alone has been used since 2005 and is known to cause side effects such as myelosuppression (reduced bone marrow activity) and pleural effusions (fluid around the lungs), but dose adjustments can help manage these. ^{1 2 4 5 6}

How is the drug combination of ASTX727 and Dasatinib unique for treating chronic myeloid leukemia?

The combination of ASTX727 (Decitabine/Cedazuridine) and Dasatinib is unique because it combines a DNA methylation inhibitor with a tyrosine kinase inhibitor, potentially enhancing treatment effectiveness for advanced-phase chronic myeloid leukemia, where single-agent therapies have limited success. ^{1 2 4 5 7}

Research Team

Elias Jabbour, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults newly diagnosed with Philadelphia chromosome or BCR-ABL positive chronic myeloid leukemia in the early chronic phase. They should have minimal prior treatment, good organ function, and an ECOG performance of 0-2. Pregnant women, those with serious heart disease, significant bleeding disorders, uncontrolled infections or hepatitis B/C are excluded.

Inclusion Criteria

Total bilirubin < 1.5 x upper limit of normal (ULN) (unless secondary to Gilbert's disease, < 2.5 x ULN)

Patients must sign an informed consent indicating awareness of the investigational nature of the study

I can take care of myself and am up and about more than half of my waking hours.

Exclusion Criteria

I do not have any uncontrolled mental health issues.

Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 460 msec)

My chronic myeloid leukemia is in an accelerated phase.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive dasatinib daily, and starting from cycle 4, also receive decitabine and cedazuridine for 3 days in each 28-day cycle

3 years

Maintenance

Participants continue to receive dasatinib daily in 28-day cycles

12 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

15 years

Follow-up at 30 days post-treatment, then every 6 months

Treatment Details

Interventions

• ASTX727
• Dasatinib

Trial Overview The trial is testing ASTX727 (a chemotherapy drug) combined with dasatinib (an enzyme blocker) to treat chronic myeloid leukemia. It aims to see if this combination can control cancer cell growth by killing cells or stopping them from dividing and spreading.

Participant Groups

Group I: Treatment (dasatinib, decitabine and cedazuridine) Experimental Treatment 2 Interventions

Patients receive dasatinib PO QD on days 1-28. Beginning cycle 4, patients also receive decitabine and cedazuridine PO QD on days 1-3. Cycles repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive dasatinib PO QD on days 1-28. Cycles repeat every 28 days for up to 12 years in the absence of disease progression or unacceptable toxicity.

ASTX727 is already approved in United States, European Union for the following indications:

Approved in United States as Inqovi for:

• Myelodysplastic Syndromes (MDS)

Approved in European Union as Inqovi for:

• Myelodysplastic Syndromes (MDS)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Astex Pharmaceuticals, Inc.

Industry Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Findings from Research

A clinical study involving 56 volunteers demonstrated that the generic dasatinib tablet (YiNiShu®) is bioequivalent to the branded version (Sprycel®) under both fasting and fed conditions, indicating similar pharmacokinetic profiles.

Both dasatinib formulations showed a good safety profile, confirming that patients can expect comparable efficacy and safety when using either version of the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. Wang, Y., Xue, J., Su, Z., et al.[2023]

Dasatinib, a multiple kinase inhibitor, is rapidly absorbed in the body after oral administration, with a peak concentration reached in about 30 minutes and a short elimination half-life of less than 4 hours, indicating efficient absorption and metabolism.

Most of dasatinib is eliminated through feces (85%), and while several metabolites are formed, they are not expected to significantly contribute to the drug's therapeutic effects, as the active metabolites do not show strong inhibitory activity against key kinases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolism and disposition of dasatinib after oral administration to humans. Christopher, LJ., Cui, D., Wu, C., et al.[2015]

Decitabine is an effective hypomethylating agent for treating acute myeloid leukemia (AML), significantly improving overall survival and response rates compared to standard care, based on results from the phase 3 DACO-016 trial with adult patients who are not eligible for standard chemotherapy.

The treatment is generally well tolerated and remains effective even in patients with adverse-risk karyotypes or TP53 mutations, making it a valuable option for those unfit for more intensive therapies, with potential for future combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. Santini, V., Lübbert, M., Wierzbowska, A., et al.[2022]

The combination of dasatinib and decitabine was found to be safe and effective in treating advanced chronic myeloid leukemia (CML), with no dose-limiting toxicities observed in a study of 30 patients.

Out of the participants, 48% achieved a major hematologic response, and those who responded had a significantly better median overall survival of 13.8 months compared to 4.65 months for non-responders, highlighting the potential of this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II study of dasatinib in combination with decitabine in patients with accelerated or blast phase chronic myeloid leukemia. Abaza, Y., Kantarjian, H., Alwash, Y., et al.[2020]

Dasatinib, approved by the FDA for treating chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL), showed a major cytogenetic response rate of 45% in chronic phase CML and significant hematologic response rates in other phases of CML and Ph(+) ALL, indicating its efficacy in patients resistant to prior therapies.

The treatment was associated with common side effects such as myelosuppression, bleeding, and fluid retention, highlighting the importance of monitoring patient safety during dasatinib therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Brave, M., Goodman, V., Kaminskas, E., et al.[2023]

Dasatinib is an effective targeted therapy for chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemia, showing strong hematologic, cytogenetic, and molecular responses in patients resistant or intolerant to imatinib.

Despite its efficacy, dasatinib can cause significant side effects like myelosuppression and pleural effusions, particularly in advanced-phase patients; however, recent dose optimization has reduced these adverse events without affecting the drug's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias]. Cony-Makhoul, P., Bergeron, A., Corm, S., et al.[2015]

In a study of 253 patients with newly diagnosed chronic-phase chronic myeloid leukemia, dasatinib (DAS) showed a higher complete cytogenetic remission rate (84%) compared to imatinib (IM) (69%), indicating DAS may be more effective in achieving initial treatment goals.

While DAS resulted in more complete cytogenetic and deeper molecular responses after 12 months, both treatments had similar overall and progression-free survival rates, with DAS associated with higher rates of hematologic toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Radich, JP., Kopecky, KJ., Appelbaum, FR., et al.[2022]

References

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

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. [2023]

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

Metabolism and disposition of dasatinib after oral administration to humans. [2015]

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

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. [2022]

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

Phase I/II study of dasatinib in combination with decitabine in patients with accelerated or blast phase chronic myeloid leukemia. [2020]

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

Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. [2023]

6. France pubmed.ncbi.nlm.nih.gov

[Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias]. [2015]

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

A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. [2022]