CIML NK Cells With Venetoclax for AML

NCT06152809 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 23-534
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

Brief Summary

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)

Conditions

Leukemia; Acute Myeloid Leukemia; Acute Myeloid Leukemia Recurrent; Leukemia, Myeloid

Keywords

Acute Myeloid Leukemia; Acute Myeloid Leukemia Recurrent; Leukemia; Leukemia, Myeloid

Outcome Measures

Primary Outcomes (2)

• Dose Limiting Toxicity (DLT)

  A DLT is defined as an adverse event (AE) that is related to the CIML NK cell infusion with venetoclax as consolidation therapy. Toxicities are to be assessed according to the CTCAEv5.

  Observing window is from Day 0 (day of CIML NK cell infusion) to Day +28

• Maximum Tolerated Dose (MTD)

  The MTD in the CIML NK cell infusion with venetoclax as consolidation therapy is determined by the number of participants who experience a DLT. See previous primary outcome measure for the DLT definition. If ≤1 DLTs are observed at dose-level 0, this dose will be the MTD. If ≥2 DLTs are observed in a cohort of 5 evaluable participants, then the MTD is considered exceeded. If this is dose level 0, dose de-escalation will take place, and 5 evaluable participants will be enrolled at dose level -1. If ≥2 DLTs are observed at dose level -1, accrual will stop.

  Observing window is from Day 0 (day of CIML NK cell infusion) to Day +28

Secondary Outcomes (7)

• Measurable Residual Disease Negative (MRD-) Rate

  At +28 days post CIML NK Infusion

• 100-day Leukemia-Free Survival (LFS)

  100 Days

• 1-year Leukemia-Free Survival (LFS)

  1 Year

• 100-day Overall Survival (OS)

  100 Days

• 1-year Overall Survival (OS)

  1 Year

Study Arms (2)

Cohort 1: Dose Level 0

EXPERIMENTAL

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.

Biological: Cytokine-Induced Memory-like Natural Killer Cells; Biological: Interleukin-2; Drug: Venetoclax

Cohort 1: Dose Level -1

EXPERIMENTAL

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.

Biological: Cytokine-Induced Memory-like Natural Killer Cells; Biological: Interleukin-2; Drug: Venetoclax

Interventions

Cytokine-Induced Memory-like Natural Killer Cells BIOLOGICAL

Allogeneic, cytokine induced memory-like natural killer cells, via intravenous infusion per protocol.

Also known as: CIML NK Cells

Cohort 1: Dose Level -1; Cohort 1: Dose Level 0

Interleukin-2 BIOLOGICAL

Recombinant, human glycoprotein, single-use 22 MIU vials, via subcutaneous (under the skin) injection per protocol.

Also known as: Aldesleukin, Proleukin, IL-2

Cohort 1: Dose Level -1; Cohort 1: Dose Level 0

Venetoclax DRUG

Selective inhibitor of BCL-2 protein, 10, 50, or 100 mg tablets, via orally per standard-of-care.

Also known as: C45H50ClN7O7S

Cohort 1: Dose Level -1; Cohort 1: Dose Level 0

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of acute myeloid leukemia (AML)
• Age ≥ 18 years old
• At time of screening patient is being treated with HMA(azacitidine or decitabine) + venetoclax therapy and has received at least 1 cycle of HMA (azacitidine or decitabine) + venetoclax. Patients can have received other lines of therapy prior to HMA + venetoclax therapy including prior chemotherapy and any prior stem cell transplant, provided that the stem cell transplant is \> 6 months prior with no ongoing need for immunosuppressive therapy for active graft-versus-host disease.
• Presence of molecular risk factors for relapse with continued HMA + venetoclax therapy as defined by any of the following present at the time of diagnosis or start of HMA + venetoclax therapy (these do not need to be present at the time the screening BM biopsy):
• ELN adverse risk karyotype: t(6;9)(p23.3;q34.1)/DEK::NUP214; t(v;11q23.3)/KMT2A-rearranged; t(9;22)(q34.1;q11.2)/BCR::ABL1; t(8;16)(p11.2;p13.3)/KAT6A::CREBBP; inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/ GATA2, MECOM(EVI1), t(3q26.2;v)/MECOM(EVI1)-rearranged; -5 or del(5q); -7; Complex karyotype, monosomal karyotype
• ELN adverse risk mutations: Any one of the following mutations: Mutated TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2
• Additional mutations associated with acquired resistance to venetoclax: Mutated NRAS, KRAS, FLT3 ITD/TKD
• ECOG performance status ≤2 (see Appendix A)
• Participants must meet the following organ function as defined below:
• Direct bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except Gilbert's or disease-related hemolysis, then \< 3 x ULN)
• AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN
• creatinine clearance ≥ 45 mL/min; calculated by the Cockcroft Gault formula
• oxygen saturation ≥ 90% on room air
• left ventricular ejection fraction ≥ 40%
• Negative pregnancy test for women of childbearing potential only.

You may not qualify if:

• Prior allogeneic stem cell transplant, organ transplant or donor lymphocyte infusion (DLI), CAR-T cell or NK cell therapy
• Persisting Grade \> 1 non hematologic toxicity related to prior therapy; however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
• Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease disease requiring any steroids \>\> the equivalent dose of 10 mg of prednisone or other immunosuppressive therapies at the time of this screening visit (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's Granulomatosis\]) and motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis). Patients with Hashimoto's thyroiditis are eligible to go on study.
• Pregnant women are excluded from this study because of the unknown teratogenic risk of CIML NK cells and IL-2 and with the potential for teratogenic or abortifacient effects by Flu/Cy chemotherapy regimen. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CIML NK cells and IL-2, breastfeeding should be discontinued if the mother is treated on this study.
• HIV-positive participants are ineligible because of the potential for pharmacokinetic interactions with anti-retroviral agents used in this study. In addition, these participants are at increased risk of lethal infections when treated with marrow suppressive therapy.
• Individuals with active uncontrolled hepatitis B or C are ineligible as they are at high risk of lethal treatment-related hepatotoxicity after conditioning therapy.
• Individuals with a history of a different malignancy are ineligible except for the following circumstances: 1. History of other malignancy and have had complete remission of disease for at least 2 years; 2. Diagnosed and treated within the past 2 years for: nonmetastatic melanoma, surgically resected (not needing systemic chemotherapy) squamous cell carcinoma of skin and nonmetastatic prostate cancer not needing systemic chemotherapy.
• History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to IL-2 or other agents used in study.
• Participants who are receiving any other investigational agents for this condition
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Prior history of Grade 2 or higher hemolytic anemia (≥ 2g decrease in hemoglobin plus laboratory evidence of hemolysis) from any cause.
• Patient was eligible for protocol per section 3.1.
• Repeat bone marrow biopsy at this time shows a complete remission (CR) or complete remission with incomplete count recovery (CRi) or morphologic leukemia free state (MLFS) (\< 5% blasts) but with presence of measurable residual disease (MRD+). MRD can be determined by either flow cytometry, next generation sequencing or PCR. Patients with only persistent DNMTA, TET2 or ASXL1 mutations will not qualify as MRD+ as these DTA mutations without other comutations are associated with clonal hematopoiesis. OR
• Repeat bone marrow biopsy at this time shows 5-19% residual myeloblasts in the bone marrow by either bone marrow aspirate or core biopsy.
• Confirmed haploidentical or fully HLA-matched related donor that is willing and eligible for non-mobilized collection.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead

Study Sites (2)

Brigham and Women's Hospital

Boston, Massachusetts, 02215, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia; Leukemia, Myeloid

Interventions

Interleukin-2; aldesleukin; venetoclax

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• Evan Chen, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Evan Chen, MD

CONTACT

(617) 632-1906; evan_chen@dfci.harvard.edu

Rizwan Romee, MD

CONTACT

(617) 632-3470; rizwan_romee@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: One group of patients, two dose levels (arms)

Study Record Dates

• First Submitted: November 22, 2023
• First Posted: December 1, 2023
• Study Start: February 20, 2024
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): November 30, 2027
• Last Updated: March 18, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (2)