ASTX727 + Venetoclax for Acute Myeloid Leukemia

Recruiting at 61 trial locations

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Taiho Oncology, Inc.

Must not be taking: Antiretrovirals, CYP3A inhibitors

Disqualifiers: HIV, Hepatitis B/C, Myeloproliferative neoplasm, others

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

Compensation: Varies

Number of Visits: 2

101 Participants Needed

Trial Summary

What is the purpose of this trial?

The Phase 1 portion of this study is a single-arm, open-label, multicenter, non-randomized interventional study to evaluate the pharmacokinetic (PK) interaction, safety, and efficacy of ASTX727 when given in combination with venetoclax for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. 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 (AUC) and maximum plasma concentration (Cmax) exposure. The Phase 2 portion of the study is to assess the efficacy of ASTX727 and venetoclax when given in combination and to evaluate potential PK interactions. Phase 2 will follow the same overall study design as Phase 1 and has two parts, Part A and Part B.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial, especially those that are strong CYP3A or P-gp inhibitors, or those with moderate or strong CYP3A inhibitor activity. It's best to discuss your current medications with the study team to see if any changes are needed.

What data supports the effectiveness of the drug combination ASTX727 and Venetoclax for treating acute myeloid leukemia?

Research shows that combining Venetoclax with Decitabine (part of ASTX727) is effective for older patients with acute myeloid leukemia, with a significant number achieving complete remission. In one study, patients receiving this combination had longer overall survival compared to those receiving Decitabine alone. ^{1 2 3 4 5}

Is the combination of ASTX727 and Venetoclax safe for humans?

The combination of Venetoclax and Decitabine (ASTX727) has been studied in patients with acute myeloid leukemia (AML), including those who are older or have relapsed disease. These studies suggest that the treatment is generally safe, but as with any medication, there may be side effects, and it is important to discuss these with your healthcare provider. ^{1 3 4 5 6}

What makes the drug ASTX727 + Venetoclax unique for treating acute myeloid leukemia?

The combination of ASTX727 (Decitabine and Cedazuridine) with Venetoclax is unique because it combines a hypomethylating agent with a BCL-2 inhibitor, which has shown promising results in older patients or those unfit for intensive chemotherapy. This regimen offers a novel approach by potentially improving outcomes in high-risk acute myeloid leukemia patients, especially those who are newly diagnosed or have relapsed. ^{2 4 5 7 8}

Research Team

Kim-Hien Dao, DO, PhD

Principal Investigator

Astex Pharmaceuticals, Inc.

Eligibility Criteria

Adults diagnosed with newly identified acute myeloid leukemia (AML) who are either 75 years or older, or between 18 to 74 with certain health issues that make intensive chemotherapy unsuitable. Participants must have a life expectancy of at least three months and be able to give informed consent. Women must not be pregnant and participants should agree to use effective contraception.

Inclusion Criteria

I am not eligible for intensive chemotherapy due to my age or health conditions.

Participants and their partners with reproductive potential must agree to use a highly effective contraceptive measure during the study and for 3 months after the last dose of study treatment, including refraining from sperm donation. Effective contraception includes methods such as oral contraceptives or double-barrier method (eg, use of a condom AND diaphragm, with spermicide)

I am not pregnant or breastfeeding and my pregnancy test was negative.

Exclusion Criteria

You cannot have eaten grapefruit, grapefruit products, Seville oranges, or starfruit within a week before the start of the trial.

I do not have any major health issues that would affect my participation in the study.

I am allergic to decitabine, cedazuridine, venetoclax, or their ingredients.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Evaluation of pharmacokinetic interaction, safety, and efficacy of ASTX727 in combination with venetoclax for newly diagnosed AML

3 cycles of 28 days each

Cycle 1: 1 visit per week, Cycle 2 and beyond: 1 visit every 2 weeks

Treatment Phase 2

Assessment of efficacy and potential PK interactions of ASTX727 and venetoclax combination

3 cycles of 28 days each

Cycle 1: 1 visit per week, Cycle 2 and beyond: 1 visit every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

Treatment Details

Interventions

• Decitabine and Cedazuridine (ASTX727)
• Venetoclax

Trial Overview The trial is testing the combination of ASTX727 (Decitabine and Cedazuridine) with Venetoclax in AML patients. It's designed in two phases: Phase 1 checks for drug interactions, while Phase 2 evaluates how well this combination works against AML.

Participant Groups

Group I: Oral administration of ASTX727 and Venetoclax combination Experimental Treatment 2 Interventions

Cycle 1: ASTX727 according to a prescribed dosing regimen and venetoclax on day 1 (100 mg daily), day 2 (200 mg daily), and days 3-28 (400 mg daily) of a 28-day cycle. Cycle 2 and beyond: ASTX727 according to a prescribed dosing regimen and venetoclax on days 1-28 (400 mg daily) of a 28-day cycle.

Who Is Running the Clinical Trial?

Taiho Oncology, Inc.

Lead Sponsor

Trials

79

Recruited

12,700+

Tim Whitten

Taiho Oncology, Inc.

Chief Executive Officer since 2018

MBA and Pharmacy degree

Harold Keer

Taiho Oncology, Inc.

Chief Medical Officer

MD, PhD

Astex Pharmaceuticals, Inc.

Lead 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

Findings from Research

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 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]

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 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]

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 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]

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]

References

1. 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]

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

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

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

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]

5. 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]

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

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

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

Utility of therapeutic drug monitoring of venetoclax in acute myeloid leukemia. [2022]

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

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. [2023]