Cytokine Induced Memory-like Natural Killer Cell Therapy after Donor Stem Cell Transplant in Treating Children and Young Adults with Relapsed Acute Myeloid Leukemia
This pilot phase I/II trial studies the side effects and to see how well cytokine induced memory-like natural killer cell works in treating children and young adults with acute myeloid leukemia that has come back (recurrent) after donor stem cell transplant. Adding an infusion of cytokine induced memory-like natural killer cells may boost the effectiveness of donor lymphocyte infusion in treating the transplant recipient and putting him/her back into remission.
Inclusion Criteria
- Relapsed AML after human leukocyte antigen (HLA)-matched or HLA-mismatched related or unrelated allogeneic hematopoietic cell transplant
- For pilot pediatric/young adult patient cohort: >= 1 and < 18 years of age
- For phase 2 adult patient cohort: >= 18 years of age
- Available original donor (same donor as used for the initial stem cell transplant) that is willing and eligible for non-mobilized collection
- Patients with known central nervous system (CNS) involvement with AML are eligible provided that they have been treated and cerebrospinal fluid (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 performance status > 60%
- Total bilirubin < 2 mg/dl
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3.0 x institutional upper limit of normal (IULN)
- Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m^2 by Cockcroft-Gault formula
- Oxygen saturation >= 90% on room air
- Not currently requiring systemic corticosteroid therapy (10 mg or less of prednisone or equivalent doses of other systemic steroids are allowed) or any other immune suppressive medications
- Women of childbearing potential must have a negative pregnancy test within 28 days prior to study registration; female and male patients (along with their female partners) must agree to use two forms of acceptable contraception, including one barrier method, during participation in the study including throughout the initial evaluation period (100 days after CIML NK cell infusion)
- Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable)
- DONOR: At least 2 years of age
- DONOR: Donor weight must be at least 15 kg
- DONOR: Same donor as used for the allogeneic hematopoietic cell transplantation (allo-HCT)
- DONOR: In general good health, and medically able to tolerate leukapheresis
- DONOR: Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative)
- DONOR: For donors < 18 years, eligible to undergo standard of care leukapheresis for DLI
Exclusion Criteria
- Acute or chronic GVHD with ongoing active systemic treatment
- Circulating blast count > 10,000/uL by morphology or flow cytometry (cyto-reductive therapies, including salvage chemotherapy, is encouraged prior to study enrollment).
- Uncontrolled bacterial or viral infections, or known human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection
- Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiography (EKG) suggestive of acute ischemia or active conduction system abnormalities
- New or progressive pulmonary infiltrates concerning for new or uncontrolled infectious process
- Known hypersensitivity to one or more of the study agents
- Received any investigational drugs within the 14 days prior to CIML NK cell infusion date
- Pregnant and/or breastfeeding
- DONOR: Active hepatitis, positive for human T-cell lymphotropic virus (HTLV), or HIV on donor viral screen
- DONOR: Pregnant
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03068819.
PRIMARY OBJECTIVES:
I. To determine the feasibility of successfully generating cytokine induced memory-like (CIML) natural killer (NK) cells concurrent with standard of care (SOC) donor lymphocyte infusion (DLI) from the original stem cell donor. (Pilot Pediatric/Young Adult Cohort)Feasibility is defined as the ability to generate and successfully infuse CIML NK cells with SOC DLI.
II. To assess the safety of administering CIML NK cells plus DLI in regards to unexpected early mortality, unacceptable graft versus host disease (GVHD), or prolonged neutropenia. (Pilot Pediatric/Young Adult Cohort)
III. To assess the safety of administering CIML NK cells plus DLI in regards to unexpected early mortality, unacceptable GVHD, or prolonged neutropenia. (Phase 2 Adult Cohort)
IV. To determine the rate of leukemia-free survival (LFS) at 6 months (+/-1 month) post CIML NK cell infusion. (Phase 2 Adult Cohort)
SECONDARY OBJECTIVES:
I. To determine complete remission (CR/CRi) rate at Day 30 after the CIML NK cell infusion using modified IWG criteria (Pilot Pediatric/Young Adult Cohort)
II. To determine the rate of leukemia-free survival (LFS) and overall survival (OS) at 100 days post CIML NK cell infusion. (Pilot Pediatric/Young Adult Cohort)
III. To determine the rate of leukemia-free survival (LFS) and overall survival (OS) at 1 year post CIML NK cell infusion. (Pilot Pediatric/Young Adult Cohort)
IV. To determine the incidence and severity of acute GVHD rates after CIML NK cell infusion. (Pilot Pediatric/Young Adult Cohort)
V. To determine the incidence and severity of chronic GVHD rates after CIML NK cell infusion. (Pilot Pediatric/Young Adult Cohort)
VI. To determine complete remission (CR/CRi) rate at Day 30 after the CIML NK cell infusion using modified IWG criteria (Phase 2 Adult Cohort)
VII. To determine the rate of leukemia-free survival (LFS) and overall survival (OS) at 100 days post CIML NK cell infusion. (Phase 2 Adult Cohort)
VIII. To determine the rate of leukemia-free survival (LFS) and overall survival (OS) at 1 year post CIML NK cell infusion. (Phase 2 Adult Cohort)
IX. To determine the incidence and severity of acute GVHD after CIML NK cell infusion. (Phase 2 Adult Cohort)
X. To determine the incidence and severity of chronic GVHD after CIML NK cell infusion. (Phase 2 Adult Cohort)
CORRELATIVE OBJECTIVES:
I. To evaluate the number, phenotype, persistence, and function of the CIML NK cells following adoptive transfer.
II. To assess functional responses of CIML NK cells to leukemia targets.
III. To assess acute myeloid leukemia (AML) blasts and the bone marrow (BM) microenvironment pre-therapy and at first relapse to identify mechanisms of NK cell immunoevasion.
IV. To define the KIR genotype of donor NK cells, and in exploratory analyses correlate with clinical endpoints.
V. To define the cytokine profiles associated with CIML NK cell plus DLI administration.
VI. To define the immune cell reconstitution following CIML NK cell plus DLI administration.
OUTLINE:
Patients receive standard of care salvage chemotherapy at -2 to -4 weeks including fludarabine intravenously (IV) over 30 minutes daily for 5 doses, cytarabine IV over 3 hours daily for 5 doses, and filgrastim subcutaneously (SC) daily for 5 doses, OR decitabine IV over 1 hour daily for 5 doses, OR another standard of care salvage chemotherapy regimen, if clinically appropriate and approved by the study principal investigator. Patients also receive standard of care donor lymphocyte (CD3+ T cells) infusion on day -1. Patients then receive CIML NK cell IV over 15-30 minutes on day 0.
After completion of study treatment, patients are followed up at 6, 9, 12, 18, 24, 36, and 48 months.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorAmanda Fishback Cashen
- Primary ID202206197
- Secondary IDsNCI-2017-01720
- ClinicalTrials.gov IDNCT03068819