Venetoclax + ASTX727 for High-Risk MDS/CMML

Overseen By Guillermo Garcia-Manero

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Antiretrovirals, CYP3A inducers

Disqualifiers: HIV, Hepatitis B/C, Cardiovascular, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and most effective dose of a new treatment combination for individuals with high-risk blood disorders, specifically myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML). The treatment combines venetoclax, a chemotherapy drug that kills or stops cancer cells from spreading, with ASTX727 (also known as Inaqovi, a mix of cedazuridine and decitabine), which helps stop cancer cell growth. The trial seeks participants who have not yet received treatment for high-risk MDS or CMML, particularly those with excessive immature blood cells. Eligible participants will take the study drugs in cycles, with close monitoring to assess the combination's effectiveness and potential side effects. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received any prior BCL2 inhibitor therapy, and you should not take strong or moderate CYP3A inducers within 7 days before starting the study treatment. Also, avoid grapefruit, Seville oranges, and Starfruit 3 days before starting the treatment. Please consult with the trial team for more details.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken any BCL2 inhibitor therapy before. Also, you should not have taken strong or moderate CYP3A inducers within 7 days before starting the study treatment.

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

Research has shown that combining venetoclax with decitabine and cedazuridine (ASTX727) is generally safe for individuals with high-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. In earlier studies, patients tolerated this treatment well, with most not experiencing severe side effects.

Common side effects included lower blood cell counts and mild stomach issues like nausea, which were managed with standard care. Side effects can vary from person to person. The treatment remains under study, with ongoing monitoring to ensure its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Venetoclax and ASTX727 for treating high-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) because it introduces a novel approach to tackling these diseases. Unlike traditional treatments that often rely on chemotherapy, Venetoclax targets and blocks BCL-2, a protein that helps cancer cells survive, while ASTX727 allows for effective oral administration of decitabine, enhancing its activity. This combination not only offers a potentially more effective mechanism of action but also provides the convenience of oral administration, which could improve patient quality of life.

What evidence suggests that this trial's treatments could be effective for high-risk MDS/CMML?

This trial will evaluate the combination of venetoclax and ASTX727 for high-risk MDS/CMML. Research has shown that venetoclax can be effective when combined with other treatments for certain blood cancers. In patients with high-risk conditions, venetoclax-based therapies have led to quick improvements and longer survival. Studies on decitabine and cedazuridine (ASTX727) found that 70% of patients with myelodysplastic syndromes (MDS) experienced some positive response, including complete or partial recovery and improved bone marrow function. These treatments work by killing cancer cells or stopping them from growing and spreading. ^{6 7 8 9 10}

Who Is on the Research Team?

Guillermo Garcia-Manero

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with untreated high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia, who have normal liver and kidney function tests, can join. They must not be pregnant, agree to contraception during the trial and for 3 months after, and cannot have had prior BCL2 inhibitor therapy or certain infections.

Inclusion Criteria

Creatinine < 2 x ULN unless related to the disease

Total bilirubin < 3 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement

I have a high-risk blood disorder with specific risk scores and may have had treatment to lower my white cell count.

Exclusion Criteria

Patient has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment

I have previously received BCL2 inhibitor therapy.

I have not taken strong or moderate CYP3A inducers in the last 7 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax orally once daily on days 1-14 and ASTX727 orally once daily on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 3-6 months for up to 5 years.

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine and Cedazuridine
• Venetoclax

Trial Overview

The trial is testing the safety and optimal dosage of venetoclax in combination with ASTX727 (cedazuridine plus decitabine) on patients. It aims to understand how these drugs work together to stop cancer cell growth by killing them or preventing their spread.

How Is the Trial Designed?

Group I: Treatment (venetoclax, ASTX727) Experimental Treatment 2 Interventions

Patients receive venetoclax orally PO QD on days 1-14. Patients also receive ASTX727 PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

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

In a study of eight pediatric patients with high-grade myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), the combination of venetoclax and 5-azacitidine was well tolerated, with gastrointestinal and hematologic adverse events being the most common.

The treatment led to positive outcomes, with six patients showing morphologic responses, including all four AML responders becoming minimal residual disease negative, suggesting that this regimen is promising and warrants further investigation in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia. Winters, AC., Maloney, KW., Treece, AL., et al.[2020]

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 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 1b study involving 44 patients with relapsed/refractory higher-risk myelodysplastic syndromes (MDS), the combination of venetoclax and azacitidine demonstrated significant activity, with a median overall survival of 12.6 months after prior treatment failure with hypomethylating agents.

The treatment resulted in hematological improvements, including complete remission in 7% of patients and transfusion independence in 36%, indicating that venetoclax plus azacitidine can provide meaningful clinical benefits for patients with limited options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Zeidan, AM., Borate, U., Pollyea, DA., et al.[2023]

In a study of 27 older patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS), the combination of azacytidine and venetoclax resulted in a median overall survival of 22.3 months, significantly higher than the 14.7 months reported in phase III trials and 5.94 months in a historical cohort treated with azacytidine alone.

The combination therapy also improved progression-free survival compared to azacytidine alone, and the results suggest that administering azacytidine and venetoclax as upfront therapy may enhance clinical benefits, even in patients with negative prognostic markers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical efficacy of azacytidine and venetoclax and prognostic impact of Tim-3 and galectin-9 in acute myeloid leukemia and high-risk myelodysplastic syndromes: A single-center real-life experience. Giudice, V., Serio, B., Ferrara, I., et al.[2023]

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]

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]

The combination of azacitidine and venetoclax is safe and well-tolerated in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia, with a recommended phase 2 dose established as azacitidine 75 mg/m2 for 5 days plus venetoclax 400 mg for 14 days.

The treatment showed a high overall response rate of 87% among the 23 enrolled patients, indicating promising preliminary activity for this combination therapy in treatment-naive and relapsed or refractory cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study. Bazinet, A., Darbaniyan, F., Jabbour, E., et al.[2022]

In a retrospective study of high-risk myelodysplastic syndromes (MDS) patients, the combination of hypomethylating agents (HMAs) and venetoclax demonstrated high response rates, indicating its potential effectiveness as a treatment option.

However, this combination therapy was also associated with a high frequency of myelosuppression, suggesting that while it may be effective, careful monitoring of blood cell counts is necessary during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax and hypomethylating agent therapy in high risk myelodysplastic syndromes: a retrospective evaluation of a real-world experience. Azizi, A., Ediriwickrema, A., Dutta, R., et al.[2022]

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 retrospective study of 35 patients with refractory and/or relapsed high-risk myelodysplastic syndrome (HR-MDS), the combination of azacytidine and a 15-day course of venetoclax resulted in a promising overall response rate of 57.2% and a median overall survival of 14 months.

The most common side effects were blood cell reductions and infections, indicating that while the treatment shows potential, myelosuppression is a significant concern that needs to be managed, especially for patients who may require further treatments like stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

15-days duration of venetoclax combined with azacitidine in the treatment of relapsed/refractory high-risk myelodysplastic syndromes: A retrospective single-center study. Mei, C., Ye, L., Ren, Y., et al.[2023]

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