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

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial tests a new treatment that combines cytokine-induced memory-like natural killer (CIML NK) cells with the drug venetoclax to determine its safety and effectiveness for people with acute myeloid leukemia (AML). The treatment involves several steps, including standard chemotherapy drugs before infusing the NK cells and adding venetoclax. This trial may suit those diagnosed with AML, currently on a specific treatment plan, and at risk for relapse. Participants should manage daily activities without severe symptoms and must be able to swallow pills. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive it.

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.

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

Research shows that cytokine-induced memory-like (CIML) natural killer (NK) cells can be safely administered to patients. Previous studies found that these cells can be derived from donor cells and used without causing serious side effects, suggesting they might be well-tolerated.

Venetoclax, a drug approved for certain types of leukemia, has been used in earlier studies with other treatments for Acute Myeloid Leukemia (AML) and was generally safe, though some patients experienced side effects.

This trial tests the combination of CIML NK cells, interleukin-2 (IL-2, which supports the immune system), and venetoclax. As an early phase study, the main goal is to assess the safety of this combination for patients. This is crucial because the combination and dosage are being tested for the first time. Overall, previous research has shown that each component is reasonably safe. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using CIML NK cells combined with Venetoclax for treating Acute Myeloid Leukemia (AML) because it introduces a novel approach to fighting this aggressive cancer. Unlike standard treatments like chemotherapy and targeted drugs such as FLT3 inhibitors, CIML NK cells leverage the body's immune system, specifically using cytokine-induced memory-like natural killer cells to target and destroy leukemia cells. This immunotherapy strategy offers a new mechanism of action, potentially improving outcomes by enhancing the body's natural cancer-fighting capabilities. Additionally, Venetoclax, which inhibits a protein that helps cancer cells survive, complements this by further weakening the cancer cells, making them more susceptible to attack by the immune system. This combination could offer a more effective and targeted treatment option for AML patients.

What evidence suggests that this trial's treatments could be effective for Acute Myeloid Leukemia?

Research has shown that a special type of immune cell, called cytokine-induced memory-like (CIML) natural killer (NK) cells, may effectively fight acute myeloid leukemia (AML). These NK cells, part of the immune system, can potentially attack cancer cells. Studies have demonstrated their ability to target and respond to AML cells, the harmful cells in this type of leukemia. In this trial, participants will receive CIML NK cells as part of their treatment regimen.

Venetoclax, another component of this trial's treatment regimen, has also proven effective against AML. Specifically, some studies reported that about 68% of patients responded to venetoclax, and around 61% experienced complete remission, meaning their cancer symptoms disappeared. By combining CIML NK cells and venetoclax, this trial aims to offer a robust approach to combating AML by leveraging the strengths of both treatments. ^{1 2 3 4 6}

Who Is on the Research Team?

Evan Chen, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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 5 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 5 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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5436500/

Cytokine-induced memory-like natural killer cells exhibit ... Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0753332223015160

Review Cytokine‐Induced Memory‐Like NK Cells It is believed that Natural killer (NK) cells play an important role in immunological first-line defense, predicting cancerous cell response to immunotherapy, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01898793

NCT01898793 | Cytokine-induced Memory-like NK Cells in ... This phase I/2 trial studies the side effects and best dose of activated natural killer cells in treating patients with relapsed or refractory acute myeloid ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05580601

Study Details | NCT05580601 | Cytokine-Induced Memory ... The objective of this study is to demonstrate that cytokine-induced memory-like natural killer cells can be generated from donor cells and infused safely into ...

5. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04354025/

Clinical Trial: NCT04354025 This phase 2 clinical trial investigates the effectiveness of cytokine-induced memory-like natural killer (CIML NK) cells in combination with ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02782546

NCT02782546 | Cytokine Induced Memory-like NK Cell ... The cytokine-induced memory like natural killer (CIML NK) cells will be infused on Day +7 without a filter or pump, slowly by gravity over at least 15 minutes.