Venetoclax + ASTX727 for Chronic Myelomonocytic Leukemia

Not currently recruiting at 39 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Lenalidomide, Decitabine, Azacitidine, others

Disqualifiers: Pregnancy, CNS disease, Active infection, 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: 1

Duration: Up to 4 cycles

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether combining two medications, decitabine and cedazuridine (ASTX727), with a third medication, venetoclax, reduces symptoms of certain bone marrow cancers more effectively than ASTX727 alone. The focus is on chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) with excess immature blood cells. Patients diagnosed with one of these conditions and a specific level of immature blood cells might be suitable candidates. The goal is to determine if this combination provides better disease control. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

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

The trial protocol does not specify if you must stop taking your current medications. However, you must stop using erythropoietin stimulating agents and thrombopoietic agents 4 weeks before starting the study treatment. Hydroxyurea is allowed until the start of therapy to control blood counts.

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

Research has shown that taking decitabine and cedazuridine (ASTX727) with venetoclax is generally safe for patients. Studies have found that this combination is well-tolerated and shows promising results for individuals with serious blood conditions like chronic myelomonocytic leukemia (CMML) or myelodysplastic syndrome (MDS) with an excess of immature blood cells. Reports indicate that patients did not experience severe side effects, making this treatment a potentially safer option for managing these conditions. Taken orally, the treatment offers more convenience and comfort for patients. Safety data for the combination is promising, suggesting a good balance between effectiveness and tolerability. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Chronic Myelomonocytic Leukemia because they offer a novel combination approach that could enhance treatment effectiveness. Venetoclax, in particular, stands out because it targets and inhibits a protein called BCL-2, which helps cancer cells survive. This is different from most standard treatments that typically involve chemotherapy or hypomethylating agents. Additionally, combining Venetoclax with ASTX727 (a combination of Decitabine and Cedazuridine) could enhance the anti-leukemic effects by concurrently disrupting cancer cell survival pathways and DNA methylation, potentially leading to better patient outcomes.

What evidence suggests that this trial's treatments could be effective for chronic myelomonocytic leukemia?

Research has shown that the combination of decitabine and cedazuridine (ASTX727), which participants in this trial may receive, can effectively treat conditions like chronic myelomonocytic leukemia (CMML). One study found that patients with CMML and myelodysplastic syndromes (MDS) had a 62% overall response rate and lived for an average of 31.7 months. Venetoclax, another treatment option in this trial, has shown promising results in blood cancers such as acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) when used with other treatments. It blocks a protein called Bcl-2, which cancer cells need to survive. This trial will test the combination of ASTX727 and venetoclax to determine if it provides a more effective treatment by reducing cancer symptoms for patients with CMML or similar conditions. ^{6 7 8 9 10}

Who Is on the Research Team?

Rory M. Shallis

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with chronic myelomonocytic leukemia or myelodysplastic/myeloproliferative neoplasm who haven't had specific previous treatments for these conditions. Participants must be able to swallow pills, have a certain level of heart and organ function, and not have uncontrolled illnesses. Pregnant women are excluded, and participants must agree to use contraception.

Inclusion Criteria

Aspartate aminotransferase (AST) serum aspartate aminotransferase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) =< 3.0 x institutional ULN OR =< 5.0 x institutional ULN for patients with liver metastases

My kidney function is within the safe range for the trial.

I am HIV-positive, on treatment, and my viral load has been undetectable for 6 months.

Exclusion Criteria

Consumption of grapefruit, grapefruit products, Seville oranges, or starfruit within 3 days prior to the initiation of study treatment and unwillingness to discontinue consumption throughout the study

I do not have another cancer that affects the safety or study of the treatment.

Pregnant women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive ASTX727 and venetoclax or ASTX727 alone in 28-day cycles

Up to 4 cycles

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 6 months for up to 5 years

Bi-annual visits

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine and Cedazuridine
• Venetoclax

Trial Overview The trial is testing if combining Venetoclax with ASTX727 (a mix of Decitabine and Cedazuridine) is more effective than ASTX727 alone in reducing symptoms of bone marrow cancer in patients with CMML or MDS/MPN with excess blasts.

How Is the Trial Designed?

Group I: Arm I (ASTX727, venetoclax) Experimental Treatment 5 Interventions

Patients receive ASTX727 PO QD on days 1-5 of each cycle and venetoclax PO QD on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy and aspiration and collection of blood samples throughout the study and undergo buccal swab sample collection at screening.

Group II: Arm II (ASTX727) Active Control 5 Interventions

Patients receive ASTX727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not have response to treatment may cross over to Arm I. Patients also undergo bone marrow biopsy and aspiration and collection of blood samples throughout the study and undergo buccal swab sample collection at screening.

Decitabine and Cedazuridine is already approved in European Union, United States for the following indications:

Approved in European Union as Inaqovi for:

• Acute myeloid leukemia (AML) in adults who are ineligible for standard induction chemotherapy

Approved in United States as ASTX727 for:

• Adult patients with newly diagnosed acute myeloid leukemia (AML) who are 75 years or older, or who have comorbidities precluding intensive induction chemotherapy

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 2 trial involving 168 patients with acute myeloid leukaemia (AML), the combination of venetoclax and a 10-day regimen of decitabine resulted in a high overall response rate of 74%, with particularly impressive results in newly diagnosed AML patients (89%).

The treatment demonstrated a manageable safety profile, with common adverse events including neutropenia and infections, and a 30-day mortality rate of only 3.6%, indicating that this combination therapy is both effective and relatively safe for older patients or those unfit for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. DiNardo, CD., Maiti, A., Rausch, CR., et al.[2021]

A 50-year-old male with relapsed acute myeloid leukemia (AML) achieved complete remission after being treated with decitabine and venetoclax as a fifth-line therapy, demonstrating the potential efficacy of this combination in difficult-to-treat cases.

Following remission, the patient successfully underwent a haploidentical transplant, resulting in an overall survival of 48.6 months, suggesting that this treatment approach may serve as a viable bridge to transplant for patients with multiresistant AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Decitabine and Venetoclax as Salvage and Bridge Therapy to Haploidentical Hematopoietic Stem Cell Transplantation in a Multiresistant Acute Myeloid Leukemia Patient. Serio, B., Giudice, V., Morini, D., et al.[2022]

Venetoclax, a BCL-2 inhibitor, shows promise in combination therapies for newly diagnosed or relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), achieving high remission rates and deep molecular responses.

Despite these encouraging results, there are concerns about side effects such as incomplete blood count recovery and increased infection rates, particularly when used with chemotherapy, and more research is needed to understand the long-term effectiveness and durability of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. Shimony, S., Stone, RM., Stahl, M.[2023]

In a study of 60 patients with high-risk MDS and AML, venetoclax demonstrated a 35% overall response rate, indicating its efficacy as a treatment option for these conditions.

However, the treatment was associated with significant hematologic toxicity, with 86.7% of patients experiencing grade 2 or higher side effects, and infections, particularly pneumonia, being the most common nonhematologic complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Real-life Turkish Experience of Venetoclax Treatment in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia. Gemici, A., Ozkalemkas, F., Dogu, MH., et al.[2022]

In a phase 2 trial involving 33 adults with newly diagnosed acute myeloid leukaemia, the combination of venetoclax with daunorubicin and cytarabine (DAV regimen) achieved a remarkable composite complete remission rate of 91% after one cycle of treatment.

The treatment was found to be safe, with no treatment-related deaths reported, although all patients experienced grade 3 or worse adverse events, such as neutropenia and thrombocytopenia, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial. Wang, H., Mao, L., Yang, M., et al.[2022]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In a real-world study of 24 patients with acute myeloid leukemia (AML) treated with the oral BCL2 inhibitor venetoclax (VEN) combined with hypomethylating agents (HMAs), 52% achieved complete remission, indicating significant efficacy for patients unfit for intensive chemotherapy.

However, the treatment was associated with a high rate of adverse drug reactions, with 79% of patients experiencing serious side effects, including a notable incidence of febrile neutropenia, which led to 3 deaths, highlighting the need for careful monitoring of safety in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database. Gozzo, L., Vetro, C., Brancati, S., et al.[2021]

In a study involving 145 older patients (median age 74) with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of venetoclax with decitabine or azacitidine resulted in a high complete remission (CR) rate of 67%, demonstrating its efficacy in this challenging population.

The treatment was well tolerated, with no cases of tumor lysis syndrome reported, and the median overall survival was 17.5 months, indicating that venetoclax combined with hypomethylating agents is a promising option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. DiNardo, CD., Pratz, K., Pullarkat, V., et al.[2021]

In a study of 22 heavily pre-treated patients with relapsed or refractory acute myeloid leukaemia (RR-AML), the combination of venetoclax and decitabine resulted in a 45.5% overall response rate, with 40.9% achieving complete remission, demonstrating its efficacy in a real-world setting.

While the treatment was effective, it was associated with significant side effects, including grade IV neutropenia and thrombocytopenia in all patients, but no deaths were attributed to the treatment side effects, indicating that the adverse effects were manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. Tong, J., Zhao, N., Hu, X., et al.[2022]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

Citations

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Efficacy of Oral Decitabine/Cedazuridine (ASTX727) in the ... Oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m 2 with a resultant clinical activity safety and efficacy ...

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NCT03306264 | Study of ASTX727 vs IV Decitabine in ... Multicenter PK study of ASTX727 versus IV decitabine. Adult participants who were candidates to receive IV decitabine were randomized 1:1 to receive the ...

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Oral Decitabine-Cedazuridine Is a Game Changer for MDS ... The oral formulation of decitabine-cedazuridine helps empower patients with MDS or CMML to maintain their quality of life from the comfort ...

4. taihooncology.com taihooncology.com/us/news/2021-09-23_astex_press_release_astx727_mos_data_presented_at_mds_international_symposium/

Astex Pharmaceuticals Presents Overall Survival Data ... Study achieved median overall survival of 31.7 months; Updated efficacy data demonstrated an overall response rate of 62%, ...

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1230 Clinical Efficacy and Safety of Oral Decitabine ... Here, we present the clinical efficacy and safety results of oral decitabine/cedazuridine from 133 patient study in MDS and CMML (ASTX727-02 ASCERTAIN study).

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05600894

NCT05600894 | Venetoclax in Combination With ASTX727 ... The combination of ASTX727 and venetoclax may be more effective in reducing the cancer signs and symptoms in patients with CMML, or MDS/MPN with excess blasts.

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121022424

A Phase I/II Study of Venetoclax in Combination with ... Conclusion: Ven+ASTX727 combination appears safe and demonstrates preliminary efficacy in pts with higher risk MDS or CMML with excess blasts. Total oral ...

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

S172: PHASE 1/2 STUDY OF ORAL DECITABINE ... The combination of ASTX727 plus venetoclax is a promising, fully oral combination that is well-tolerated and demonstrates a high response rate in higher-risk ...

9. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(22)01427-6/fulltext

MDS-520 A Phase I/II Study of Venetoclax in Combination ... Conclusions: Ven+ASTX727 combination appears safe and demonstrates preliminary efficacy in pts with higher risk MDS or CMML with excess blasts. Total-oral ...

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

An all-oral regimen of decitabine-cedazuridine (DEC-C) ... The all-oral regimen of DEC-C plus VEN resulted in comparable safety, response, and survival rates to parenteral AZA plus VEN in pts with newly diagnosed AML.