CIML NK Cells + Venetoclax for Acute Myeloid Leukemia

Recruiting at 1 trial location

Overseen By Evan Chen, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must be taking: HMA, Venetoclax

Must not be taking: CYP3A inhibitors, Investigational agents

Disqualifiers: Autoimmune disease, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 46

10 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to test the safety and to explore the effectiveness of infusing cytokine- induced memory-like (CIML) natural killer (NK) cells in combination with Interleukin-2 (IL-2) and standard-of-care venetoclax as a treatment for Acute Myeloid Leukemia (AML). Names of the study therapies involved in this study are: * Lymphodepleting therapy with Fludarabine and Cyclophosphamide prior to CIML NK cell infusion * CIML NK (a cellular therapy) * IL-2 (a recombinant, human glycoprotein) * Venetoclax (a selective inhibitor of BCL-2 protein)

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you must not take venetoclax or HMA for at least 7 days before the second screening visit. Also, you cannot be on systemic steroid therapy over 10 mg of prednisone or equivalent on the day of NK cell infusion.

What data supports the effectiveness of the treatment CIML NK Cells + Venetoclax for Acute Myeloid Leukemia?

Research shows that cytokine-induced memory-like NK cells, when used alone, have enhanced ability to fight leukemia cells and have led to complete remission in some patients with acute myeloid leukemia. Additionally, venetoclax, when used in combination with other treatments, has shown to improve immune responses in AML patients. ^{1 2 3 4 5}

Is the combination of CIML NK Cells and Venetoclax safe for humans?

Venetoclax has been studied in various settings for acute myeloid leukemia and is generally considered safe, though it can cause side effects like gastrointestinal issues and blood-related problems. Serious adverse reactions, including infections and febrile neutropenia (fever with low white blood cell count), have been reported, but no fatal drug-related events were noted in the studies. ^{6 7 8 9 10}

How is the CIML NK Cells + Venetoclax treatment different from other treatments for acute myeloid leukemia?

The CIML NK Cells + Venetoclax treatment is unique because it uses cytokine-induced memory-like natural killer (CIML NK) cells, which are preactivated with specific cytokines to enhance their ability to fight leukemia cells. This approach leverages the body's immune system to target cancer cells more effectively, offering a novel immunotherapy option compared to traditional chemotherapy. ^{1 3 5 11 12}

Research Team

Evan Chen, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults with Acute Myeloid Leukemia (AML) who have had at least one cycle of HMA + venetoclax therapy, are not candidates for stem cell transplant, and have a suitable donor for NK cells. Participants must be in good health otherwise, with proper organ function and no severe allergies or autoimmune diseases.

Inclusion Criteria

Agree to use adequate contraception

No evidence of ongoing hemolysis

No severe allergic reactions attributed to compounds of similar chemical or biologic composition to IL-2 or other agents used in study

Exclusion Criteria

I do not have any ongoing or active infections.

I have not received any live vaccines in the past 6 months.

I am not taking strong medications that affect liver enzymes, except for antifungals.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

2 visits (in-person)

Lymphodepleting Therapy

Participants receive lymphodepleting chemotherapy with Fludarabine and Cyclophosphamide prior to CIML NK cell infusion

5 days

Daily visits (in-person)

CIML NK Cell Infusion and Treatment

Participants receive CIML NK cells, IL-2, and Venetoclax as consolidation therapy

3-4 weeks

Hospitalization for CIML NK infusion, followed by daily visits for IL-2 and Venetoclax administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Visits on Days 42, 60, 100 and months 6, 9, and 12

Treatment Details

Interventions

• Cytokine-Induced Memory-like Natural Killer Cells
• Interleukin-2
• Venetoclax

Trial Overview The trial is testing the safety and potential effectiveness of CIML NK cells combined with IL-2 and venetoclax as consolidation therapy in AML patients. It includes lymphodepleting therapy before infusing the NK cells to see if this can help treat AML more effectively.

Participant Groups

Group I: Cohort 1: Dose Level 0 Experimental Treatment 3 Interventions

A maximum tolerated dose (MTD) will be established, and dosage will start at dose level 0. 5-10 participants at dose level 0 will complete: * Baseline visit. * Bone marrow biopsies: at screening visit #2, end of treatment, and at discretion of PI. * Days -6 through -2: predetermined doses of standard-of-care lymphodepleting chemotherapy. * Day 0: Predetermined dose of CIML NK cells 1x daily. Hospitalization for up to 3 to 4 weeks for CIML NK infusion. * Days 0 through 12: Predetermined dose of IL-2 1x daily every other day for up to 7 doses. * Day 7 through Day 21: Predetermined dose of Venetoclax 1 x daily. * If ≤1 dose-limiting toxicities (DLTs) are observed, this dose will be the MTD, and 5 additional participants will be enrolled. * Follow-up visits: Days 42, 60, 100 and months 6, 9, and 12.

Group II: Cohort 1: Dose Level -1 Experimental Treatment 3 Interventions

De-escalation to dose level -1 will be conducted per protocol if DLTs occur in Cohort 1 dose Level 0. Participants will complete: * Baseline visit. * Bone marrow biopsies: at screening visit #2, end of treatment, and at discretion of PI. * Days -6 through -2: predetermined doses of standard-of-care lymphodepleting chemotherapy. * Day 0: Predetermined dose of CIML NK cells 1x daily. Hospitalization for up to 3 to 4 weeks for CIML NK infusion. * Days 0 through 12: Predetermined dose of IL-2 1x daily every other day for up to 7 doses. * Day 7 through Day 21: Predetermined dose of Venetoclax 1 x daily. * Follow-up visits: Days 42, 60, 100 and months 6, 9, and 12.

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Findings from Research

Cytokine-induced memory-like NK cells show enhanced ability to produce interferon-γ and kill leukemia cells, making them a promising option for treating acute myeloid leukemia (AML).

In a first-in-human phase 1 clinical trial, memory-like NK cells were successfully expanded in AML patients, leading to clinical responses in five out of nine patients, including four complete remissions, indicating their potential effectiveness as an immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Romee, R., Rosario, M., Berrien-Elliott, MM., et al.[2021]

In a clinical trial involving 15 patients with relapsed/refractory acute myeloid leukemia (AML), the use of donor-derived memory-like (ML) NK cells combined with N-803 (an IL-15 superagonist) was well tolerated and resulted in an impressive 87% of patients achieving a composite complete response within 28 days.

The ML NK cells showed significant expansion and persistence, remaining the dominant lymphocyte population for over 2 months post-transplant, and exhibited enhanced antitumor functions compared to conventional NK cells, indicating their potential as an effective immunotherapy strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia. Berrien-Elliott, MM., Foltz, JA., Russler-Germain, DA., et al.[2023]

In a phase 1 trial involving 9 pediatric and young adult patients with relapsed acute myeloid leukemia (AML) after hematopoietic cell transplantation, donor-derived memory-like natural killer (ML NK) cells showed significant antileukemic activity, leading to complete remission in 4 out of 8 evaluable patients by day 28.

The ML NK cells expanded and persisted for over 3 months without significant toxicity, suggesting that this approach, combined with donor lymphocyte infusions, could be a promising new immunotherapy for relapsed AML in a post-transplant setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant. Bednarski, JJ., Zimmerman, C., Berrien-Elliott, MM., et al.[2023]

In a study of 82 adult patients with acute myeloid leukemia (AML), 57% were able to start venetoclax treatment safely in an outpatient setting, demonstrating its feasibility outside of the hospital.

The risk of tumor lysis syndrome (TLS) was very low, with only 2.1% of patients experiencing TLS after starting venetoclax, and 98% of patients did not require hospitalization for TLS within the first week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. Palmer, S., Patel, A., Wang, C., et al.[2023]

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 and alvocidib was found to be safe and tolerable in patients with relapsed/refractory Acute Myeloid Leukemia (AML), with no maximum tolerated dose reached, although significant gastrointestinal side effects were common.

The overall response rate to this treatment was modest, with only 11.4% achieving complete or incomplete remission, indicating that while the combination is safe, it may not significantly enhance efficacy compared to using each drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia. Jonas, BA., Hou, JZ., Roboz, GJ., et al.[2023]

In a real-world study of 24 patients with acute myeloid leukemia (AML) treated with the oral BCL2 inhibitor venetoclax (VEN) combined with hypomethylating agents (HMAs), 52% achieved complete remission, indicating significant efficacy for patients unfit for intensive chemotherapy.

However, the treatment was associated with a high rate of adverse drug reactions, with 79% of patients experiencing serious side effects, including a notable incidence of febrile neutropenia, which led to 3 deaths, highlighting the need for careful monitoring of safety in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database. Gozzo, L., Vetro, C., Brancati, S., et al.[2021]

A trifunctional natural killer cell engager (NKCE) has been developed that specifically targets and kills CD123+ acute myeloid leukemia (AML) cells, showing promise as a potential treatment for this type of cancer.

This NKCE represents a novel approach to harnessing the body's immune system to fight leukemia, which could lead to more effective therapies for patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Trifunctional Natural Killer Cell Engager Can Target CD123+ Leukemia. [2023]

References

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

Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Lymphocyte Exhaustion in AML Patients and Impacts of HMA/Venetoclax or Intensive Chemotherapy on Their Biology. [2022]

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

Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia. [2023]

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

Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant. [2023]

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

Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia. [2022]

6. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Venetoclax-Based Induction Therapy in Acute Myeloid Leukemia]. [2023]

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

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. [2023]

8. 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]

9. England pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database. [2021]

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

A Trifunctional Natural Killer Cell Engager Can Target CD123+ Leukemia. [2023]

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

An overview of the potential strategies for NK cell-based immunotherapy for acute myeloid leukemia. [2018]