Venetoclax + ASTX727 for Pediatric AML

Overseen By Amber Gibson, DO

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, others

Disqualifiers: CNS pathology, Active infections, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 21-28 days per cycle

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two medications—ASTX727 (a combination of decitabine and cedazuridine) and venetoclax—to determine the best dose for treating pediatric acute myeloid leukemia (AML) that has returned or resisted treatment. The trial targets children and teens aged 2 to 18 with this specific type of leukemia who can swallow pills. Participants will take these medications on a specific schedule to assess the safety and effectiveness of this combination. 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 therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that you cannot take other anti-cancer therapies except for hydroxyurea during the first two cycles. Also, medications metabolized by CDA need review and possible adjustment around the time of taking cedazuridine.

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

Research is investigating the safety and effectiveness of combining ASTX727 and venetoclax for treating acute myeloid leukemia (AML). Venetoclax has shown success in other conditions, suggesting potential safety. However, information is still being collected on the safety of this combination for children with AML.

In studies with adults, these drugs have been used together safely, though some side effects, such as low blood cell counts and infections, were noted, which are common with chemotherapy. While these findings are encouraging, more research is needed to confirm safety in children.

As this trial is in an early stage, researchers are primarily focused on identifying the safest dose. Early trials involve close monitoring to manage any side effects and adjust doses if needed. Participants will be closely observed to ensure the treatment remains safe for them. ^{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 pediatric acute myeloid leukemia (AML) because it offers a novel approach to treatment. Unlike standard chemotherapy, Venetoclax targets and inhibits a protein called BCL-2, which helps cancer cells survive. ASTX727, on the other hand, is an oral drug that enhances the effects of Venetoclax by modifying DNA methylation, potentially increasing the cancer cells' sensitivity to treatment. This dual-action strategy aims to tackle the disease more effectively and with potentially fewer side effects than traditional treatments.

What evidence suggests that this trial's treatments could be effective for pediatric AML?

Studies have shown that venetoclax effectively treats acute myeloid leukemia (AML), even in children, by targeting and killing cancer cells. In this trial, participants will receive a combination of venetoclax with ASTX727, which includes two drugs: cedazuridine and decitabine. Research suggests that this combination may enhance venetoclax's effectiveness in killing cancer cells in patients whose AML has returned. Early findings from other studies indicate that this combination might help treat more severe cases of AML, offering hope for better treatment options for children with relapsed AML. ^{1 2 3 4 6}

Who Is on the Research Team?

Amber Gibson, DO

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for pediatric patients aged 2-18 with relapsed/refractory Acute Myeloid Leukemia. They must have a certain level of blasts in their blood or bone marrow, be able to swallow pills, and meet specific health criteria including liver and kidney function. Pregnant females can't participate, and all participants must agree to use contraception.

Inclusion Criteria

At least one parent or LAR must provide signature of informed consent and there must be documentation of assent by the subject, as age appropriate, before completing any study-related procedures

I can swallow pills.

My kidney function tests are within the normal range for my age and sex.

Exclusion Criteria

I have a history of cancer, but it is either in remission, a non-melanoma skin cancer, or a carcinoma in situ.

Known or suspected hypersensitivity to specific medications

My current medications are reviewed for interactions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ASTX727 and venetoclax. ASTX727 is taken orally on Days 1-5 of Cycle 1, and venetoclax is taken daily with water and a meal.

21-28 days per cycle

Multiple visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ASTX727
• Venetoclax

Trial Overview The study aims to find the right dose of ASTX727 combined with venetoclax for children who have AML that has come back after treatment or didn't respond to previous treatments. It's an early-phase trial focusing on dosage, safety, how the body processes the drugs (pharmacokinetics), and how they affect leukemia (pharmacodynamics).

How Is the Trial Designed?

Group I: ASTX727/venetoclax Experimental Treatment 2 Interventions

On Days 1-5 of Cycle 1, you will take ASTX727 by mouth with a glass of water. Participants must fast (not eat or drink anything but water, black coffee, or tea) for at least 2 hours before and for 2 hours after taking ASTX727. For 4 hours before dosing and 4 hours after dosing, participants should not take antacids or any other medicine that can change the amount of acid in your stomach. Days 1-21 or 1-28 depending on dose level, of all cycles beginning with Cycle 2. The study doctor will tell participants which of these schedules participants will follow. Venetoclax should be taken with water and a meal at around the same time each day.

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+

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 phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

In a study of 6 children with refractory or relapsed acute myeloid leukemia (AML), the combination of venetoclax, azacitidine, and cladribine (VAC regimen) resulted in significant treatment responses, with 4 achieving complete remission and 1 showing partial remission.

Despite severe side effects like grade IV neutropenia and thrombocytopenia, there were no treatment-related deaths or infections, indicating that the VAC regimen is both effective and safe for this vulnerable patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. DU, WW., Liu, SX., Wang, Y., et al.[2023]

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]

The combination of venetoclax with hypomethylating agents (HMA) has significantly improved survival rates in patients with acute myeloid leukemia (AML), as demonstrated in a phase 3 study.

Venetoclax is also safe when added to standard intensive regimens, leading to high remission rates and measurable residual disease negativity in both newly diagnosed and relapsed/refractory AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. Ball, BJ., Koller, PB., Pullarkat, V.[2023]

In a study of 12 older adults (median age 74) with acute myeloid leukemia (AML), individualized dosing of venetoclax using therapeutic drug monitoring (TDM) showed that many patients had higher plasma concentrations than previously reported, suggesting a need for dose adjustments based on individual factors.

The study found a negative correlation between body surface area (BSA) and venetoclax concentrations, indicating that smaller patients, particularly those over 75 years old, may benefit from TDM to optimize treatment and enhance safety, especially when taking CYP3A4 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utility of therapeutic drug monitoring of venetoclax in acute myeloid leukemia. Kobayashi, M., Yasu, T., Suzaki, K., et al.[2022]

In a study comparing older adults with newly diagnosed acute myeloid leukemia (AML), those treated with the combination of decitabine (DEC) and venetoclax (VEN) had a significantly longer median overall survival of 13.4 months compared to 8.3 months for those receiving DEC alone.

The combination therapy also resulted in a higher response rate of 70.3% versus 24.3% for DEC monotherapy, indicating that DEC+VEN is more effective in treating AML without increasing short-term mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. Kwag, D., Cho, BS., Bang, SY., 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 study of 18 pediatric and young adult patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL), venetoclax demonstrated a complete remission rate of 61%, indicating its potential efficacy in this population.

No new safety concerns were identified with venetoclax, with myelosuppression being the most common side effect, and no deaths occurred within 30 days of starting treatment, suggesting it is a safe option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Gibson, A., Trabal, A., McCall, D., et al.[2022]

In a retrospective study of 40 patients with relapsed/refractory acute myeloid leukemia (AML) treated with venetoclax, 76% of those who survived more than two cycles achieved neutrophil recovery, indicating a positive response to the treatment.

Venetoclax demonstrated safety and efficacy in advanced AML, with a median overall survival of 5.5 months for all patients and 6.5 months for those who survived beyond two months, suggesting it can be a viable option for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax is safe and efficacious in relapsed/refractory AML. Ganzel, C., Ram, R., Gural, A., et al.[2021]

In a study of 81 patients with acute myeloid leukemia (AML) receiving venetoclax with decitabine or azacitidine, 72.8% experienced infections, with the most common pathogens being Candida albicans and Klebsiella pneumonia.

The study found that the incidence of infectious complications was lower with this treatment compared to conventional chemotherapy, and high leukemia burden and fever were identified as significant risk factors for developing infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia. Zhu, LX., Chen, RR., Wang, LL., 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]

Citations

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Venetoclax: a new player in the treatment of children with high ... After its first clinical application in chronic lymphocytic leukemia,3 venetoclax has shown efficacy in acute myeloid leukemia (AML) models.

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Venetoclax: a new player in the treatment of children with ... After its first clinical application in chronic lymphocytic leukemia, venetoclax has shown efficacy in acute myeloid leukemia (AML) models. Myeloid blasts ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-10826

Venetoclax in Combination with ASTX727 for the ... Giving venetoclax in combination with ASTX727 may kill more cancer cells in pediatric patients with relapsed or refractory AML. Eligibility Criteria ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04817241

Testing Oral Decitabine and Cedazuridine (ASTX727) in ... Giving ASTX727 in combination with venetoclax may help in the treatment of patients with higher-risk acute myeloid leukemia. Detailed Description. PRIMARY ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12350645/

Comprehensive view on chemotherapy-free management ... Phase II trial of 10-day ASTX727 (decitabine/cedazuridine) with venetoclax for relapsed or refractory acute myeloid leukemia. Blood. 2023 ...