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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of two drugs, ASTX727 (Decitabine/Cedazuridine) and dasatinib (Sprycel), to evaluate their effectiveness in treating a specific type of chronic myeloid leukemia (CML) linked to certain genetic changes. These drugs aim to stop cancer cells from growing and spreading. The trial seeks participants recently diagnosed with Philadelphia chromosome or BCR-ABL positive CML who have received minimal treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that ASTX727, a combination of decitabine and cedazuridine, is generally well-tolerated. This drug mix effectively treats certain blood cancers and has a high success rate, with manageable side effects. Low blood cell counts are a common issue, but this is often expected with cancer treatments and can be monitored.

Studies have shown that dasatinib is safe and has been used for years to treat chronic myeloid leukemia. Some patients may experience side effects like fluid retention or low blood cell counts, but these are usually manageable. Long-term studies indicate that most patients handle dasatinib well, and it remains effective over time.

In summary, both ASTX727 and dasatinib are generally safe with known, manageable side effects. Those considering joining a trial should know that these treatments have been studied for safety, but discussing personal risks with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ASTX727 and dasatinib for chronic myeloid leukemia (CML) because it introduces a fresh approach with decitabine and cedazuridine. Unlike traditional treatments, which often focus solely on tyrosine kinase inhibitors like dasatinib, this combination incorporates decitabine and cedazuridine, offering a new mechanism that may enhance the overall effectiveness. Decitabine is a hypomethylating agent, which can potentially reprogram cancer cells to stop growing. By combining these agents, there is hope for improved outcomes and increased survival rates for patients with CML.

What evidence suggests that ASTX727 and dasatinib might be effective for chronic myeloid leukemia?

Research has shown that dasatinib, which participants in this trial will receive, effectively treats chronic myeloid leukemia (CML). About 77% of patients using dasatinib reached a major treatment goal within a year, and after five years, 83% of these patients were still doing well. In this trial, participants will also receive ASTX727, a combination of decitabine and cedazuridine, starting from cycle 4. Earlier studies have shown promising results with ASTX727, with 53% of patients with specific genetic changes experiencing improvements. Together, these treatments have the potential to manage CML effectively. ^{3 4 6 7 8}

Who Is on the Research Team?

Elias Jabbour, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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, 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10428441/

S172: PHASE 1/2 STUDY OF ORAL DECITABINE ... In patients with cytogenetic abnormalities at diagnosis, 53% achieved cytogenetic response. The median duration of response was 23 months. After a median follow ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03306264?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(NSC-127716))&rank=2&tab=results

Study of ASTX727 vs IV Decitabine in Participants With ... Participants with MDS or CMML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on ...

3. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/833/499481/A-Phase-2-Study-of-the-Fully-Oral-Combination-of

A Phase 2 Study of the Fully Oral Combination of ASTX727 ... A Phase 2 Study of the Fully Oral Combination of ASTX727 (Decitabine/Cedazuridine) Plus Venetoclax for Older and/or Unfit Patients with Acute Myeloid Leukemia

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6504

An all-oral regimen of decitabine-cedazuridine (DEC-C) ... The 30- and 60-day mortality rates were 3.0% and 9.9%, respectively. PK data confirmed no drug-drug interactions between oral DEC-C and VEN.

5. thelancet.com thelancet.com/journals/lanhae/article/PIIS2352-3026(23)00338-1/abstract

Oral decitabine–cedazuridine versus intravenous ... Primary endpoint of total exposure of oral decitabine–cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66–105·60), indicating equivalent ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04657081

Study Details | NCT04657081 | Pharmacokinetics, Safety, ... The primary purpose of the study is to rule out drug-drug interactions between ASTX727 and venetoclax combination therapy by evaluating area under the curve ( ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12378960/

Efficacy and safety of oral decitabine/cedazuridine in the ... Real‐world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03813186?term=ASTX727&rank=5

NCT03813186 | Effect of Food on Blood Levels of ASTX727 This study is designed to examine blood levels of ASTX727, a fixed-dose combination tablet containing the combination of cedazuridine (100 mg) and decitabine ( ...