Cytokine-induced Memory-like NK Cells in Combination With Chemotherapy in Pediatric Patents With Refractory or Relapsed AML

NCT04354025 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: 20-x130
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase 2 clinical trial investigates the effectiveness of cytokine-induced memory-like natural killer (CIML NK) cells in combination with FLAG chemotherapy as a treatment for refractory or relapsed AML. Previous studies in adults with AML sowed successful induction of remission and a previous phase 1 study demonstrated that CIML NK cells can be used safely in pediatric patients. This phase 2 study uses FLAG chemotherapy to lower leukemic burden and suppress the recipient's immune system to provide an optimal environment for CIML NK cell expansion and anti-leukemic activity.

Conditions

Refractory Acute Myeloid Leukemia; Relapsed Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Response rate (complete remission (CR) plus complete remission with incomplete blood count recovery (CRi))

  * Complete remission (CR) requires all of the following: * Bone marrow: * Morphologically leukemia free state (≤ 5% myeloblasts) with normal maturation of all cell lines. Persistent dysplasia may be noted * Peripheral blood: * Platelets ≥ 100,000/uL * Neutrophils ≥ 1000/uL * Complete remission with incomplete blood count recovery (CRi): * All of the above criteria for CR must be met, except that absolute neutrophils \<1000/μL or platelets \<100,000 /μL in the blood.

  Day 28

• Percentage of patients able to proceed to stem cell transplant

  Up to 60 days

Secondary Outcomes (6)

• Disease-free survival (DFS)

  Up to 2 years

• Overall survival (OS)

  Up to 2 years

• Percentage of patients who achieve minimum residual disease (MRD)-negative status

  Day 28

• Safety of regimen as measured by number of adverse events

  From Day 0 to Day 100

• Duration of remission

  Up to 2 years

Study Arms (2)

Recipient: FLAG + CIML NK Cells + IL-2

EXPERIMENTAL

-The recipient will begin a chemotherapy regimen of fludarabine, cytarabine and GCSF starting on Day -7. The haploidentical donor identified by HLA matching of the immediate family members will undergo non-mobilized large volume (20 L) leukapheresis on Day -1, and the NK cell product will be infused into the recipient on Day 0. CIML NK cells will be infused at maximum cell dose of 10 x 106/kg. Subcutaneous IL-2 will begin approximately 2-4 hours after infusion and will continue every other day through Day 12 for a total of 7 doses.

Biological: Cytokine induced memory-like NK cells; Drug: Fludarabine; Drug: Ara-C; Drug: G-CSF; Drug: Interleukin-2

Donor:

OTHER

-On Day -1 (one day before the planned NK cell infusion), peripheral blood mononuclear cells will be collected by a single standard apheresis over 4-5 hours (with a target volume of at least 20 L) from the identified haploidentical donor. The apheresis procedure will be done as per standard institutional procedures (which may include placement of a central line if necessary). If the goal minimum NK cell dose will not be met based on the initial assessment of the leukapheresis product, a second collection/procedure may be performed.

Procedure: Leukapheresis

Interventions

Cytokine induced memory-like NK cells BIOLOGICAL

-The CIML NK cells (maximum dose capped at 10 x 106/kg, minimum dose allowed is 0.5 x 106/kg) will be infused on Day 0 without a filter or pump.

Also known as: CIML NK cells

Recipient: FLAG + CIML NK Cells + IL-2

Fludarabine DRUG

-Fludarabine (dose: 30 mg/m\^2 per dose) will be given daily beginning on Day -7 for a total of 5 doses administered as an IV infusion over 30 minutes.

Recipient: FLAG + CIML NK Cells + IL-2

Ara-C DRUG

-Ara-C (dose: 2000mg/m\^2 per dose) will be given daily for a total of 5 doses administered as IV infusion over 3 hours, starting the same day as fludarabine.

Also known as: Cytarabine

Recipient: FLAG + CIML NK Cells + IL-2

G-CSF DRUG

-Filgrastim (dose: 5 mcg/kg per dose to a maximum of 300 mcg) will be given subcutaneously daily for a total of 5 doses starting the same day as fludarabine and ara-C.

Also known as: Filgrastim

Recipient: FLAG + CIML NK Cells + IL-2

Interleukin-2 DRUG

-IL-2 will be administered subcutaneously at a dose of 1 million units/m2 every other day from Day 0 to Day +12 (7 doses total).

Also known as: IL-2

Recipient: FLAG + CIML NK Cells + IL-2

Leukapheresis PROCEDURE

-Donor only

Donor:

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Refractory AML without complete remission (CR) after induction therapy (primary induction failure) or relapsed AML after obtaining a CR. Disease defined by one of the following:
• \*≥ 5% blasts in the bone marrow (M2/M3 bone marrow), with or without extramedullary disease
• \*absolute blast count greater than 1,000 per microliter in the peripheral blood with or without extramedullary disease.
• Age requirement for pediatric cohort: 1-21 years of age.
• Available HLA-haploidentical donor that meets the following criteria:
• Related donor (parent, sibling, offspring, or offspring of sibling)
• At least 18 years of age
• HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A\&B locus.
• In general, good health and medically able to tolerate leukapheresis required for harvesting the NK cells for this study.
• Negative for hepatitis, HTLV, and HIV on donor viral screen
• Not pregnant
• Voluntary written consent to participate in this study
• Patients with known CNS involvement with AML are eligible provided that they have been treated and CSF is clear for at least 2 weeks prior to enrollment into the study. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment.
• Karnofsky/Lansky performance status \> 50 %
• Adequate organ function as defined below:

You may not qualify if:

• Relapsed after allogeneic transplantation.
• Isolated extramedullary relapse
• Circulating blast count \>30,000/µL by morphology or flow cytometry (cytoreductive therapies including leukapheresis or hydroxyurea are allowed).
• Patients with any of the following diagnoses:
• Down's syndrome
• Acute promyelocytic leukemia (APL)
• Juvenile myelomonocytic leukemia (JMML)
• Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B or C infection.
• Known hypersensitivity to one or more of the study agents.
• Received any investigational drugs within the 14 days prior to the first dose of fludarabine.
• Pregnant

Sponsors & Collaborators

• Washington University School of Medicine: lead

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

fludarabine; Cytarabine; Granulocyte Colony-Stimulating Factor; Filgrastim; Interleukin-2; Leukapheresis

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Interleukins; Lymphokines; Cytapheresis; Biological Therapy; Therapeutics; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques

Study Officials

• Jeffrey Bednarski, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 16, 2020
• First Posted: April 21, 2020
• Study Start: June 30, 2023
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): July 31, 2028
• Last Updated: April 4, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share