Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML After Allogeneic Hematopoietic Cell Transplant

Study Overview
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Brief Summary
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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.

Official Title
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Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML After Allogeneic Hematopoietic Cell Transplant in Children and Adults

Conditions
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Acute Myeloid Leukemia in Children

Intervention / Treatment
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* Drug: CIML NK Cell Infusion
* Procedure: CD3+ T Cell Product Infusion


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CIML NK cell after T cell DLT (Pilot Pediatric/Young Adult Cohort)<br>The recipient will receive standard of care salvage chemotherapy consisting of fludarabine (or cladribine if shortage), cytarabine, and G-CSF (FLAG) to be started 2 to 4 weeks prior to the CIML NK cell infusion. 5-day decitabine is an acceptable alternative for FLAG, and another standard of care salvage chemotherapy regimen, if clinically appropriate and approved by the study PI, may be used. The donor will undergo non-mobilized leukapheresis on Day -2 or -1. Standard of care DLI (1 x 10^6 CD3+ cells/kg) will be given fresh on day -1. A second cycle of therapy may be administered > 30 days after the administration of the first course of protocol therapy to maintain response or to treat persistent/relapsed AML, if a patient continues to meet the inclusion/exclusion criteria. Chemotherapy may be omitted before a second infusion of DLI and CIML NK cells. In the setting of GVHD following the first cycle of therapy, the T cell DLI may be omitted, and ML NK cells administered. | Drug: CIML NK Cell Infusion<br>* -Day 0<br>Procedure: CD3+ T Cell Product Infusion<br>* -Day -1<br>|
| Experimental: CIML NK cell after T cell DLT (Phase 2 Adult Cohort)<br>The recipient will receive lymphodepleting chemotherapy with fludarabine (or cladribine if shortage) and cyclophosphamide beginning on day -7. The donor will undergo non-mobilized leukapheresis on Day -2 or -1. T cell dose per standard of care institutional practices and physician discretion will be given frozen for administration on day 30. A second cycle of therapy may be administered > 30 days after the administration of the first course of protocol therapy to maintain response or to treat persistent/relapsed AML, if a patient continues to meet the inclusion/exclusion criteria. Chemotherapy may be omitted before a second infusion of DLI and CIML NK cells. In the setting of GVHD following the first cycle of therapy, the T cell DLI may be omitted, and ML NK cells administered. The date of the second NK cell infusion will be considered a second Day 0. | Drug: CIML NK Cell Infusion<br>* -Day 0<br>Procedure: CD3+ T Cell Product Infusion<br>* -Day -1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | -Will be considered successful if doses above the minimum can be delivered in at least 9 of 12 patients. Target and minimum doses are: T cell DLI (5x106/kg with a minimum dose of 1x106/kg) and CIML NK cells (dose capped at 10x106/kg with a minimum dose of 0.5x106/kg). | Completion of all patients through Day 0 (estimated to be 102 months) | 
| Safety of administering CIML NK cells plus T cell DLT as measured by unexpected early mortality (Pilot Pediatric/Young Adult Cohort) | Patients will be continually assessed for unexpected early mortality (as assessed at Day +30 and Day +100 after CIML NK cell infusion), associated with the study treatment. The expected rate of early mortality is 20% and the maximum allowable rate is 45%. | Up to Day 100 | 
| Safety of administering CIML NK cells plus T cell DLT as measured by unacceptable GVHD (Pilot Pediatric/Young Adult Cohort) | -The expected rate of GVHD is 20% and the maximum allowable rate is 45%. | Up to 12 months | 
| Safety of administering CIML NK cells plus T cell DLT as measured by prolonged neutropenia (Pilot Pediatric/Young Adult Cohort) | -If any patient has persistent neutropenia at 8 weeks post CIML NK cell infusion (ANC < 500/ul persisting for > 2 weeks), patients would be evaluated with a BM biopsy to assess for AML recurrence vs. GVHD vs. loss of donor chimerism. If cytopenias were not explained by these or other causes, and possibly related to CIML NK cells, the study would be suspended and reviewed for safety of continuation. | 8 weeks post CIML NK infusion | 
| Safety of administering CIML NK cells plus T cell DLT as measured by unexpected early mortality (Phase 2 Adult Cohort) | Patients will be continually assessed for unexpected early mortality (as assessed at Day +30 and Day +100 after CIML NK cell infusion), associated with the study treatment. The expected rate of early mortality is 20% and the maximum allowable rate is 45%. | Up to Day 100 | 
| Safety of administering CIML NK cells plus T cell DLT as measured by unacceptable GVHD (Phase 2 Adult Cohort) | -The expected rate of GVHD is 20% and the maximum allowable rate is 45%. | Up to 12 months | 
| Safety of administering CIML NK cells plus T cell DLT as measured by prolonged neutropenia (Phase 2 Adult Cohort) | -If any patient has persistent neutropenia at 8 weeks post CIML NK cell infusion (ANC < 500/ul persisting for > 2 weeks), patients would be evaluated with a BM biopsy to assess for AML recurrence vs. GVHD vs. loss of donor chimerism. If cytopenias were not explained by these or other causes, and possibly related to CIML NK cells, the study would be suspended and reviewed for safety of continuation. | 8 weeks post CIML NK infusion | 
| Rate of leukemia-free survival (LFS) (Phase 2 Adult Cohort) | -LFS is defined as the time from achievement of CR/CRi to the time of relapse, death in remission, or last follow-up. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission rate (CR/CRi) (Pilot Pediatric/Young Adult Cohort) | 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. | Day 30 | 
| Rate of leukemia-free survival (LFS) (Pilot Pediatric/Young Adult Cohort) | -LFS is defined as the time from achievement of CR/CRi to the time of relapse, death in remission, or last follow-up. | 100 days post CIML NK cell infusion | 
| Overall survival (OS) (Pilot Pediatric/Young Adult Cohort) | -OS is defined as the time from the date of Day 0 until death from any cause. | 100 days post CIML NK cell infusion | 
| Rate of leukemia-free survival (LFS) (Pilot Pediatric/Young Adult Cohort) | -LFS is defined as the time from achievement of CR/CRi to the time of relapse, death in remission, or last follow-up. | 1 year post CIML NK cell infusion | 
| Overall survival (OS) (Pilot Pediatric/Young Adult Cohort) | -OS is defined as the time from the date of Day 0 until death from any cause. | 1 year post CIML NK cell infusion | 
| Incidence and severity of acute GVHD rates (Pilot Pediatric/Young Adult Cohort) | -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). | Day 14 through 6 months | 
| Incidence and severity of acute GVHD rates (Pilot Pediatric/Young Adult Cohort) | -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). | Day 14 through 6 months | 
| Incidence and severity of chronic GVHD rates (Pilot Pediatric/Young Adult Cohort) | -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). | Day 100 through 12 months | 
| Complete remission rate (CR/CRi) (Phase 2 Adult Cohort) | 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. | Day 30 | 
| Rate of leukemia-free survival (LFS) (Phase 2 Adult Cohort) | -LFS is defined as the time from achievement of CR/CRi to the time of relapse, death in remission, or last follow-up. | 100 days post CIML NK cell infusion | 
| Overall survival (OS) (Phase 2 Adult Cohort) | -OS is defined as the time from the date of Day 0 until death from any cause. | 100 days post CIML NK cell infusion | 
| Rate of leukemia-free survival (LFS) (Phase 2 Adult Cohort) | -LFS is defined as the time from achievement of CR/CRi to the time of relapse, death in remission, or last follow-up. | 1 year post CIML NK cell infusion | 
| Overall survival (OS) (Phase 2 Adult Cohort) | -OS is defined as the time from the date of Day 0 until death from any cause. | 1 year post CIML NK cell infusion | 
| Incidence and severity of acute GVHD rates (Phase 2 Adult Cohort) | -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). | Day 14 through 6 months | 
| Incidence and severity of chronic GVHD rates (Phase 2 Adult Cohort) | -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). | Day 100 through 12 months |