Azacitidine + Venetoclax + NK Cells for Acute Myeloid Leukemia

Recruiting at 1 trial location

Overseen By Abhishek Maiti, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: High-dose steroids

Disqualifiers: CNS leukemia, Active infections, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination treatment for people with acute myeloid leukemia (AML), a type of blood cancer. Researchers aim to determine if adding natural killer (NK) cells—immune cells that fight cancer and infections—to the drugs Azacitidine (a chemotherapy drug) and Venetoclax (a targeted therapy) can better control the disease. The trial consists of two parts: one to find the optimal dose and another to test it further in those who can't tolerate strong chemotherapy. It suits patients with AML who cannot undergo intensive chemotherapy or stem cell transplant. 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 innovative therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it does mention that certain supportive care medications like hydroxyurea and cytarabine are allowed, and high-dose systemic steroids or immunosuppressive therapy should not be taken within a week of the first NK cell infusion.

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

Research shows that combining Azacitidine, Venetoclax, and natural killer (NK) cells is generally safe. Previous studies on NK cell therapies have shown they are well-tolerated, causing few side effects. In patients with acute myeloid leukemia (AML), positive responses have appeared in 25% to 88% of cases, which is encouraging. Azacitidine and Venetoclax are already used together to treat AML and have established safety records. This trial is in an early phase, focusing mainly on safety, so researchers closely monitor the treatment for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of azacitidine, venetoclax, and allogeneic NK cells for treating acute myeloid leukemia (AML) because it introduces a novel approach for patients who can't endure intensive chemotherapy or stem-cell transplants. Unlike traditional treatments that focus solely on chemotherapy, this combination integrates azacitidine and venetoclax, which work together to halt leukemia cell growth, with natural killer (NK) cells that enhance the immune system's ability to target and destroy cancer cells. This innovative strategy not only aims to be more effective by targeting cancer from multiple fronts but also offers a potentially safer and more tolerable option for older or frail patients.

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

Research shows that combining Azacitidine and Venetoclax holds promise for treating acute myeloid leukemia (AML). Studies have found that these drugs effectively target and destroy cancer cells. In this trial, participants will receive Azacitidine, Venetoclax, and natural killer (NK) cells. NK cells, which fight cancer and infections, might enhance the drug combination's effect. Early results suggest that NK cells help the body more effectively attack leukemia cells. This combination aims to harness the body's immune response alongside cancer-fighting drugs to better control AML. ^{1 2 3 4 5}

Who Is on the Research Team?

Abhishek Maiti, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults diagnosed with Acute Myeloid Leukemia (AML) or related conditions, who have relapsed or don't respond to standard treatments. It's also open to older patients unfit for intensive chemotherapy. Participants must not have certain infections, severe heart issues, other active cancers, or be pregnant. They should agree to use contraception and understand the study.

Inclusion Criteria

I agree to use birth control during and after the study for the time required.

I have a history of certain blood disorders but haven't had specific treatments for MDS.

I have been diagnosed with AML or MDS/AML with 10-19% blasts.

Exclusion Criteria

I do not have severe stomach or metabolic issues affecting medication absorption.

I do not have any health, mental, or social issues that would affect my study participation.

I do not have active hepatitis B, hepatitis C, or HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of azacitidine, venetoclax, and allogeneic NK cells to evaluate safety and determine the optimal dose

4-6 weeks

Dose Expansion

Participants receive the combination of azacitidine, venetoclax, and allogeneic NK cells at the determined optimal dose to evaluate efficacy

6 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• NK Cells
• Venetoclax

Trial Overview The trial tests if adding Natural Killer (NK) cells from healthy donors to Azacitidine and Venetoclax treatment can better control AML. NK cells are part of the immune system that helps fight cancer.

How Is the Trial Designed?

Group I: Dose Expansion Experimental Treatment 3 Interventions

Dose Expansion to evaluate the combination of azacitidine, venetoclax and allogeneic NK cells in older/unfit participants with AML ineligible for intensive chemotherapy or allogeneic stem-cell transplantation (allo SCT).

Group II: Dose Escalation Experimental Treatment 3 Interventions

Dose Escalation to evaluate the combination of azacitidine, venetoclax and allogeneic NK cells in older/unfit participants with AML ineligible for intensive chemotherapy or allogeneic stem-cell transplantation (allo SCT).

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a study of 50 adults with acute myeloid leukemia (AML) in Mexico and Peru, venetoclax-based therapy showed a high complete response rate of 78.6% in newly diagnosed patients and 45.5% in those with relapsed/refractory disease, indicating its efficacy in treating AML.

The median overall survival was 9.6 months for newly diagnosed patients and 8 months for relapsed/refractory patients, suggesting that venetoclax is a viable treatment option even in real-world settings, despite common hematologic toxicities and dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. Gómez-De León, A., Demichelis-Gómez, R., Pinedo-Rodríguez, A., et al.[2022]

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

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. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

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]

Outpatient induction therapy using low-dose venetoclax combined with itraconazole and azacitidine is feasible and safe for newly diagnosed acute myeloid leukemia (ND-AML) patients, with 77.7% of participants completing the first treatment cycle as outpatients.

The treatment showed promising efficacy, with a composite complete response rate of 53.9% after the first cycle and 85.7% after the second cycle, indicating that this regimen could be a viable option for patients eligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. De la Garza-Salazar, F., Colunga-Pedraza, PR., Gómez-Almaguer, D., et al.[2023]

In a study of 57 elderly patients (average age 69.9 years) with acute myeloid leukemia, the combination of venetoclax and azacitidine (VEN + AZA) showed a high overall response rate of 87.5% and a complete remission (CR) rate of 68.8%, indicating strong efficacy in this population.

The treatment was associated with a median overall survival (OS) of 11.5 months, and achieving minimal residual disease (MRD) negativity (<0.1%) was more common with VEN + AZA compared to traditional chemotherapy, although older patients (≥75 years) and those with higher ECOG scores faced more challenges in achieving MRD negativity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. Yu, H., Wang, C., Lei, Y., et al.[2023]

In a study of 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

In a study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05834244

NCT05834244 | A Phase Ib Trial of Azacitidine, Venetoclax ... To learn if adding a healthy person's natural killer (NK) cells to the combination of Azacitidine and Venetoclax can help to control AML. NK cells are ...

2. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2022-0941.html

A phase Ib trial of Azacitidine, Venetoclax and Allogeneic ... To learn if adding a healthy person's natural killer (NK) cells to the combination of Azacitidine and Venetoclax can help to control AML.

3. ash.confex.com ash.confex.com/ash/2023/webprogram/Paper182885.html

Paper: Azacitidine, Venetoclax and Allogeneic NK Cells in ... Natural killer (NK) cells bridge the innate and adaptive immune system and play a major role in graft-vs-leukemia (GVL) effect responsible for ...

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

Comprehensive view on chemotherapy-free management ... SAR443579, a natural killer (NK)-cell engager with three binding ... Azacitidine, venetoclax and allogeneic NK cells in newly diagnosed acute ...

5. listcorp.com listcorp.com/asx/chm/chimeric-therapeutics-limited/news/advent-aml-phase-1b-clinical-trial-update-3189951.html

ADVENT-AML Phase 1B clinical trial update ... natural killer (NK) cells to the combination of Azacitidine and Venetoclax can help to control AML. NK cells are cancer- and infection ...