Venetoclax + ASTX727 for Chronic Myelomonocytic Leukemia

Recruiting in Palo Alto (17 mi)

+33 other locations

Overseen by Rory M. Shallis

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Cancer Institute (NCI)

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

Disqualifiers: Pregnancy, CNS disease, Active infection, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing if a combination of two drugs, ASTX727 and venetoclax, is more effective than ASTX727 alone in treating certain bone marrow cancers. It focuses on patients with CMML and MDS/MPN who have too many immature blood cells. ASTX727 helps produce normal blood cells and kills abnormal ones, while venetoclax blocks a protein that cancer cells need to survive. Venetoclax is an anticancer drug used to treat lymphomas and leukemias, but it has severe side effects.

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.

What data supports the idea that Venetoclax + ASTX727 for Chronic Myelomonocytic Leukemia is an effective drug?

The available research shows that Venetoclax combined with decitabine-based treatments has been effective in treating acute myeloid leukemia (AML), especially in older patients or those who cannot undergo intensive chemotherapy. For instance, in one study, 67% of patients achieved complete remission, and the combination was well tolerated. Although the studies focus on AML, the success in similar blood-related cancers suggests potential effectiveness for Chronic Myelomonocytic Leukemia as well. ^{1 2 3 4 5}

What safety data is available for the treatment of Venetoclax combined with Decitabine or ASTX727?

The safety data for Venetoclax combined with Decitabine or ASTX727 (also known as Inaqovi) primarily comes from studies involving patients with acute myeloid leukemia (AML). Common adverse events reported include nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. Serious adverse drug reactions were noted, including febrile neutropenia and infections like sepsis. In a real-world setting, 84.4% of patients experienced hematological toxicities and infections. No tumor lysis syndrome was observed in a large phase 1b study. The combination was generally well tolerated in elderly patients with AML, with a significant portion achieving complete remission. ^{2 3 4 6 7}

Is Venetoclax a promising drug for treating Chronic Myelomonocytic Leukemia?

Venetoclax is a promising drug because it has shown success in treating similar blood cancers like acute myeloid leukemia and chronic lymphocytic leukemia. It works well when combined with other treatments, helping patients who can't undergo intensive chemotherapy. It has been effective in high-risk patients and has a good safety profile. ^{2 6 8 9 10}

Research Team

Rory M. Shallis

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• Decitabine and Cedazuridine (Hypomethylation Agent)
• Venetoclax (B-cell lymphoma-2 (BCL-2) inhibitor)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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]

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 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 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 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]

References

1. Switzerland 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. [2022]

2. England 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. [2021]

3. New Zealand 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. [2022]

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

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. [2021]

5. England 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. [2022]

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

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database. [2021]

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

A Real-life Turkish Experience of Venetoclax Treatment in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia. [2022]

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

10. Switzerland 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. [2023]