Acute Myeloid Leukemia
Conditions
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.
Interventions
Day 0 and possible second cycle \> 30 days after the first course
PROCEDURECD3+ T Cell Product Infusion
Day -1 and possible second cycle \> 30 days after the first course (Pilot Pediatric/Young Adult Cohort). Day 30 and possible second cycle \>30 days after the first course (Phase 2 Adult Cohort)
PROCEDURELeukapheresis
On Day -2 or -1
Sponsors
Washington University School of Medicine
National Cancer Institute (NCI)
Wugen, Inc.
Children's Discovery Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of Successfully Generating CIML NK Cells With Standard of Care (SOC) DLI From the Original Stem Cell Donor as Measured by the Number of Participants That Had Successful Doses Infused (Pilot Pediatric/Young Adult Cohort) | Completion of all recipients through Day 0 | -Feasibility is defined as the ability to generate and successfully infuse CIML NK cells with SOC donor lymphocyte infusion (DLI). Will be considered successful if doses above the minimum can be delivered in at least 18 of 24 patients. Target and minimum CIML doses are maximum capped at 20x10\^6/kg with a minimum dose of 0.5x10\^6 kg. |
| Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Unexpected Early Mortality (Pilot Pediatric/Young Adult Cohort) | Up to Day 100 | Unexpected early mortality is defined as deaths that occur through day 100 that are possibly, probably, or definitely related to the study treatment. |
| Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Unacceptable Graft Versus Host Disease (GVHD) (Pilot Pediatric/Young Adult Cohort) | From day 14 through month 6 | Unacceptable GVHD is defined as grade IV acute GVHD as assessed by the Minnesota Grading Scale or grade D acute GVHD as assessed by the CIBMTR Grading Scale. |
| Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Prolonged Neutropenia (Pilot Pediatric/Young Adult Cohort) | 8 weeks post CIML NK infusion | Prolonged neutropenia is defined as an absolute neutrophil count \<500/μL persisting for \> 2 weeks. |
| Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Unexpected Early Mortality (Phase 2 Adult Cohort) | Up to Day 100 | Unexpected early mortality is defined as deaths that occur through day 100 that are possibly, probably, or definitely related to the study treatment. |
| Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Unacceptable GVHD (Phase 2 Adult Cohort) | From day 14 through month 6 | Unacceptable GVHD is defined as grade IV acute GVHD as assessed by the Minnesota Grading Scale or grade D acute GVHD as assessed by the CIBMTR Grading Scale. |
| Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Prolonged Neutropenia (Phase 2 Adult Cohort) | 8 weeks post CIML NK infusion | Prolonged neutropenia is defined as an absolute neutrophil count \<500/μL persisting for \> 2 weeks. |
| Kaplan-Meier Estimate of Percentage of Participants With Leukemia-Free Survival (LFS) (Phase 2 Adult Cohort) | 6 months | -LFS is defined as the time from achievement of CR/CRi to the time of relapse, death in remission, or last follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission Rate (CR/CRi) (Pilot Pediatric/Young Adult Cohort) | Day 30 | * Complete remission (CR):Morphologically leukemia free state (i.e. bone marrow with \<5% blasts by morphologic criteria and no blasts with Auer rods, no evidence of extramedullary leukemia) and absolute neutrophil count ≥1000 /μL and platelets ≥100,000 /μL. Patient must be independent of transfusions * Complete remission with incomplete blood count recover (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. |
| Complete Remission Rate (CR/CRi) (Phase 2 Adult Cohort) | Day 30 | * Complete remission (CR):Morphologically leukemia free state (i.e. bone marrow with \<5% blasts by morphologic criteria and no blasts with Auer rods, no evidence of extramedullary leukemia) and absolute neutrophil count ≥1000 /μL and platelets ≥100,000 /μL. Patient must be independent of transfusions * Complete remission with incomplete blood count recover (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. |
| Kaplan-Meier Estimate of Percentage of Participants With Leukemia-Free Survival (LFS) (Pilot Pediatric/Young Adult Cohort) | 100 days post CIML NK cell infusion | -LFS is defined as the time from achievement of CR/CRi to the time of relapse, death in remission, or last follow-up. |
| Kaplan-Meier Estimate of Percentage of Participants With Leukemia-Free Survival (LFS) (Phase 2 Adult Cohort) | 100 days post CIML NK cell infusion | -LFS is defined as the time from achievement of CR/CRi to the time of relapse, death in remission, or last follow-up. |
| Kaplan-Meier Estimate of Percentage of Participants With Overall Survival (OS) (Pilot Pediatric/Young Adult Cohort) | 100 days post CIML NK cell infusion | -OS is defined as the time from the date of Day 0 until death from any cause. |
| Kaplan-Meier Estimate of Percentage of Participants With Overall Survival (OS) (Phase 2 Adult Cohort) | 100 days post CIML NK cell infusion | -OS is defined as the time from the date of Day 0 until death from any cause. |
| Incidence and Severity of Acute GVHD Rates as Assessed on the Minnesota Grading Scale (Pilot Pediatric/Young Adult Cohort) | Day 14 through 6 months | * Incidence and severity of acute GVHD will be assessed based on the Minnesota grading scale. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s). * The Minnesota Grading scale is graded with I, II, III, IV. Grade I is the least severe and Grade IV is the most severe. |
| Incidence and Severity of Acute GVHD Rates as Assessed on the CIBMTR Grading Scale (Pilot Pediatric/Young Adult Cohort) | Day 14 through 6 months | * Incidence and severity of acute GVHD will be assessed based on the CIBMTR grading scale. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s). * The CIBMTR grading scale is graded with A, B, C, or D. Grade A is considered the least severe with Grade D being the most severe. |
| Incidence and Severity of Chronic GVHD Rates (Pilot Pediatric/Young Adult Cohort) | Day 100 through 12 months | * Incidence and severity of chronic GVHD will be assessed based on the NIH consensus criteria and global severity scoring system. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s). * Severity is graded with mild, moderate, or severe chronic GVHD. |
| Incidence and Severity of Acute GVHD Rates as Assessed on the Minnesota Grading Scale (Phase 2 Adult Cohort) | Day 14 through 6 months | * Incidence and severity of acute GVHD will be assessed based on the CIBMTR grading scale. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s). * The Minnesota Grading scale is graded with I, II, III, IV. Grade I is the least severe and Grade IV is the most severe. |
| Incidence and Severity of Acute GVHD Rates as Assessed on the CIBMTR Grading Scale (Phase 2 Adult Cohort) | Day 14 through 6 months | * Incidence and severity of acute GVHD will be assessed based on the CIBMTR grading scale. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s). * The CIBMTR grading scale is graded with A, B, C, or D. Grade A is considered the least severe with Grade D being the most severe. |
| Incidence and Severity of Chronic GVHD Rates (Phase 2 Adult Cohort) | Day 100 through 12 months | * Incidence and severity of chronic GVHD will be assessed based on the NIH consensus criteria and global severity scoring system. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s). * Severity is graded with mild, moderate, or severe chronic GVHD. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAmanda Cashen, M.D.
Washington University School of Medicine
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 54 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 55 Participants |
| Region of Enrollment United States | 28 participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 14 / 19 | 14 / 15 | 0 / 28 |
| other Total, other adverse events | 19 / 19 | 15 / 15 | 0 / 28 |
| serious Total, serious adverse events | 5 / 19 | 10 / 15 | 0 / 28 |
Outcome results
None listed