Clinical trial NCT03068819: Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML After Allogeneic Hematopoietic Cell Transplant
Official title: Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML After Allogeneic Hematopoietic Cell Transplant in Children and Adults
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: Wugen, Inc.
name: Children's Discovery Institute
First posted: 2017-03-03
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Donor Lymphocyte Infusion (DLI) following salvage chemotherapy is the one of the most widely used treatment approaches in patients who relapse after allogeneic hematopoietic cell transplant (allo-HCT). However, the complete remission (CR) rates and long term survival remain very poor in these patients and, therefore, there is an unmet need to develop more effective treatment approaches in patients who relapse after allo-HCT.

Based on the initial promising results with our ongoing cytokine-induced memory-like (CIML) natural killer (NK) cell trial, the investigators hypothesize that combining the CIML NK cells with DLI approach will significantly enhance the graft versus leukemia and therefore potentially provide potentially curative therapy for these patients with otherwise extremely poor prognosis. Combining CIML NK cells with the DLI platform will also potentially allow these adoptively transferred cells to persist for longer duration as they should not be rejected by donor T cells as the CIML NK cells are derived from the same donor. The use of CIML NK cells is unlikely to lead to excessive graft versus host disease (GVHD) as previous studies have not been associated with excessive GVHD rates.


Eligibility criteria: Recipient Inclusion Criteria:

* Relapsed AML after HLA-matched 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 %
* Adequate organ function as defined below:

  * Total bilirubin \< 2 mg/dL
  * AST(SGOT)/ALT(SGPT) \< 3.0 x IULN
  * Creatinine within normal institutional limits OR creatinine clearance \> 60 mL/min/1.73 m2 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 IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Recipient 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 HIV, Hepatitis B, or Hepatitis C infection.
* Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or 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 Inclusion Criteria:

* At least 18 years of age
* Same donor as used for the allo-HCT
* In general good health, and medically able to tolerate leukapheresis
* Ability to understand and willingness to sign an IRB approved written informed consent document

Donor Exclusion Criteria:

* Active hepatitis, positive for HTLV, or HIV on donor viral screen
* Pregnant

Primary outcomes:
measure: Feasibility of regimen defined as the number of participants who are successfully infused with T cell DLT and CIML NK cells (Pilot Pediatric/Young Adult Cohort)
timeFrame: Completion of all patients through Day 0 (estimated to be 102 months)
measure: Safety of administering CIML NK cells plus T cell DLT as measured by unexpected early mortality (Pilot Pediatric/Young Adult Cohort)
timeFrame: Up to Day 100
measure: Safety of administering CIML NK cells plus T cell DLT as measured by excess acute or chronic GVHD (Pilot Pediatric/Young Adult Cohort)
timeFrame: Up to 12 months
measure: Safety of administering CIML NK cells plus T cell DLT as measured by prolonged neutropenia (Pilot Pediatric/Young Adult Cohort)
timeFrame: 8 weeks post CIML NK infusion
measure: Safety of administering CIML NK cells plus T cell DLT as measured by unexpected early mortality (Phase 2 Adult Cohort)
timeFrame: Up to Day 100
measure: Safety of administering CIML NK cells plus T cell DLT as measured by unacceptable GVHD (Phase 2 Adult Cohort)
timeFrame: Up to 12 months
measure: Safety of administering CIML NK cells plus T cell DLT as measured by prolonged neutropenia (Phase 2 Adult Cohort)
timeFrame: 8 weeks post CIML NK infusion
measure: Rate of leukemia-free survival (LFS) (Phase 2 Adult Cohort)
timeFrame: 6 months
Secondary outcomes:
measure: Complete remission rate (CR/CRi) (Pilot Pediatric/Young Adult Cohort)
timeFrame: Day 30
measure: Rate of leukemia-free survival (LFS) (Pilot Pediatric/Young Adult Cohort)
timeFrame: 100 days post CIML NK cell infusion
measure: Overall survival (OS) (Pilot Pediatric/Young Adult Cohort)
timeFrame: 100 days post CIML NK cell infusion
measure: Rate of leukemia-free survival (LFS) (Pilot Pediatric/Young Adult Cohort)
timeFrame: 1 year post CIML NK cell infusion
measure: Overall survival (OS) (Pilot Pediatric/Young Adult Cohort)
timeFrame: 1 year post CIML NK cell infusion
measure: Incidence and severity of acute GVHD rates (Pilot Pediatric/Young Adult Cohort)
timeFrame: Day 14 through 6 months
measure: Incidence and severity of acute GVHD rates (Pilot Pediatric/Young Adult Cohort)
timeFrame: Day 14 through 6 months
measure: Incidence and severity of chronic GVHD rates (Pilot Pediatric/Young Adult Cohort)
timeFrame: Day 100 through 12 months
measure: Complete remission rate (CR/CRi) (Phase 2 Adult Cohort)
timeFrame: Day 30
measure: Rate of leukemia-free survival (LFS) (Phase 2 Adult Cohort)
timeFrame: 100 days post CIML NK cell infusion
measure: Overall survival (OS) (Phase 2 Adult Cohort)
timeFrame: 100 days post CIML NK cell infusion
measure: Rate of leukemia-free survival (LFS) (Phase 2 Adult Cohort)
timeFrame: 1 year post CIML NK cell infusion
measure: Overall survival (OS) (Phase 2 Adult Cohort)
timeFrame: 1 year post CIML NK cell infusion
measure: Incidence and severity of acute GVHD rates (Phase 2 Adult Cohort)
timeFrame: Day 14 through 6 months
measure: Incidence and severity of chronic GVHD rates (Phase 2 Adult Cohort)
timeFrame: Day 100 through 12 months
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Amanda Cashen, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bednarski JJ, Zimmerman C, Berrien-Elliott MM, Foltz JA, Becker-Hapak M, Neal CC, Foster M, Schappe T, McClain E, Pence PP, Desai S, Kersting-Schadek S, Wong P, Russler-Germain DA, Fisk B, Lie WR, Eisele J, Hyde S, Bhatt ST, Griffith OL, Griffith M, Petti AA, Cashen AF, Fehniger TA. Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant. Blood. 2022 Mar 17;139(11):1670-1683. doi: 10.1182/blood.2021013972.