SNDX-5613 + ASTX727 + Venetoclax for Acute Myeloid Leukemia

Overseen By Ghayas Issa, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Menin inhibitors

Disqualifiers: Uncontrolled conditions, Active infection, others

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

Compensation: Varies

Number of Visits: Unknown

43 Participants Needed

Trial Summary

What is the purpose of this trial?

Part 1b of this clinical research study is to find the highest tolerable dose of SNDX-5613 that can be given in combination with ASTX727 (a combination of the drugs decitabine/cedazuridine) and venetoclax for patients with acute myeloid leukemia (AML) or those with a mixed phenotype acute leukemia with a myeloid phenotype (MPAL). Part 2 of this study is to learn if the dose of study drugs found in Part 1b can help to control AML/MPAL

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but it does not allow other chemotherapeutic or anti-leukemic agents during the study, except for certain cases like intrathecal chemotherapy or hydroxyurea. You should discuss your current medications with the study team to see if they are allowed.

What data supports the effectiveness of the drug combination SNDX-5613, ASTX727, and Venetoclax for treating acute myeloid leukemia?

Research shows that combining Venetoclax with Decitabine or Azacitidine is effective for older patients with acute myeloid leukemia, achieving high remission rates and longer survival compared to Decitabine alone. ^{1 2 3 4 5}

Is the combination of SNDX-5613, ASTX727, and Venetoclax safe for humans?

The combination of Venetoclax with decitabine (ASTX727) has been studied in elderly patients with acute myeloid leukemia and was generally well tolerated, with common side effects including nausea, diarrhea, and fatigue. No serious safety concerns like tumor lysis syndrome were observed in these studies. ^{1 2 3 6 7}

What makes the drug combination of SNDX-5613, ASTX727, and Venetoclax unique for treating acute myeloid leukemia?

This drug combination is unique because it includes SNDX-5613, a novel component not commonly used in standard treatments for acute myeloid leukemia, alongside ASTX727 and Venetoclax, which have shown promising results in older patients or those unfit for intensive chemotherapy. The combination aims to enhance treatment efficacy by targeting different mechanisms involved in leukemia cell survival. ^{2 3 4 8 9}

Research Team

Ghayas Issa, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for individuals aged 12 and older, weighing at least 40kg, with relapsed/refractory acute myeloid leukemia (AML) or mixed phenotype acute leukemia with a myeloid phenotype. Participants must have an ECOG performance status of ≤2, be on certain antifungal medications, and not be taking other strong CYP3A4 inhibitors/inducers. They should agree to contraception use during the study and for three months after. Exclusions include active malignancy under treatment, severe gastrointestinal/metabolic conditions affecting drug absorption, recent significant cardiovascular events, uncontrolled medical conditions or infections.

Inclusion Criteria

I am a male who is sterile or will use contraception during and 3 months after the study.

I am taking certain antifungal medications and no other strong medications that affect drug metabolism.

My leukemia has returned or is not responding to treatment.

Exclusion Criteria

I have severe acute or chronic graft-versus-host disease.

I am currently being treated for another cancer.

I haven't had a heart attack, severe heart issues, or a stroke in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Finding (Part 1b)

Determine the highest tolerable dose of SNDX-5613 in combination with ASTX727 and venetoclax

Varies

Frequent visits for dose escalation and monitoring

Treatment (Part 2)

Assess the efficacy of the determined dose of SNDX-5613 in combination with ASTX727 and venetoclax

Multiple cycles, each cycle is 28 days

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• ASTX727
• SNDX-5613
• Venetoclax

Trial Overview The trial is testing the highest tolerable dose of SNDX-5613 in combination with ASTX727 (decitabine/cedazuridine) and venetoclax in patients with AML or MPAL. The goal is to determine if this oral drug combination can control these types of leukemia effectively.

Participant Groups

Group I: Venetoclax Experimental Treatment 1 Intervention

Tablets by mouth on Days 1-14 of each cycle.

Group II: SNDX-5613 Experimental Treatment 1 Intervention

Capsules by mouth 2 times every day (about 12 hours apart).

Group III: ASTX727 Experimental Treatment 1 Intervention

Tablets by mouth on Days 1-5 of each cycle.

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+

Syndax Pharmaceuticals, Inc.

Collaborator

Trials

5

Recruited

220+

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

Syndax Pharmaceuticals

Industry Sponsor

Trials

49

Recruited

2,700+

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]

Venetoclax combined with azacitidine or low-dose cytarabine (LDAC) is associated with significantly lower costs per patient achieving complete remission (CR) or complete remission with incomplete blood count recovery (CRi) compared to other treatments for newly diagnosed acute myeloid leukemia (AML) patients who cannot undergo intensive chemotherapy.

The estimated costs per patient achieving CR + CRi were $473,960 for venetoclax + azacitidine and $428,071 for venetoclax + LDAC, which are substantially lower than the costs for azacitidine ($1,197,438) and other therapies, indicating a more cost-effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Costs per patient achieving remission with venetoclax-based combinations in newly diagnosed patients with acute myeloid leukemia ineligible for intensive induction chemotherapy. Choi, M., Song, J., Bui, CN., et al.[2022]

A case of early-relapsed high-risk T-cell acute lymphoblastic leukemia (T-ALL) with high BCL-2 expression was successfully treated with a combination of decitabine and venetoclax, leading to complete remission (CR).

The results suggest that decitabine and venetoclax may work synergistically in treating BCL-2 positive acute lymphoblastic leukemia, indicating a potential new therapeutic strategy for this high-risk group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia. Zappone, E., Cencini, E., Defina, M., et al.[2020]

In a phase 1 study involving 38 pediatric patients aged 3-22 with relapsed or refractory acute myeloid leukemia, the combination of venetoclax and high-dose cytarabine showed promising efficacy, with 70% of patients achieving complete remission at the recommended phase 2 dose.

The study identified 360 mg/m2 of venetoclax as the recommended dose, but also reported significant safety concerns, including a 66% incidence of febrile neutropenia and one treatment-related death, highlighting the need for careful monitoring in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. Karol, SE., Alexander, TB., Budhraja, A., et al.[2021]

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 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]

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

Costs per patient achieving remission with venetoclax-based combinations in newly diagnosed patients with acute myeloid leukemia ineligible for intensive induction chemotherapy. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. [2021]

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

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

9. 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]