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

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ClinicalTrials.gov Identifier: NCT03068819
Recruitment Status : Recruiting
First Posted : March 3, 2017
Last Update Posted : December 17, 2020
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

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.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia in Children Drug: CIML NK Cell Infusion Procedure: CD3+ T Cell Product Infusion Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML After Allogeneic Hematopoietic Cell Transplant in Children and Adults
Actual Study Start Date : October 23, 2017
Estimated Primary Completion Date : May 31, 2023
Estimated Study Completion Date : May 31, 2023


Arm Intervention/treatment
Experimental: CIML NK cell after T cell DLT (Pilot Pediatric/Young Adult Cohort)
  • The recipient will receive standard of care salvage chemotherapy consisting of fludarabine, cytarabine, and G-CSF (FLAG) (or 5 day decitabine as an acceptable alternative) to be started 2 to 4 weeks prior to the CIML NK cell infusion, with Day -1 the day of T cell DLI, and Day 0 denoting the CIML NK cell infusion day. The donor will undergo non-mobilized large volume (20L) leukapheresis on Day -2 or -1, anticipating processing for T cell DLI and NK cell isolation on Day -1.
  • A second cycle of therapy may be administered if the patient shows evidence of AML > 30 days after the administration of the first course of protocol therapy, and if they continue to meet the inclusion/exclusion criteria. Salvage 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
-Day 0

Procedure: CD3+ T Cell Product Infusion
-Day -1

Experimental: CIML NK cell after T cell DLT (Phase 2 Adult Cohort)
  • The recipient will receive standard of care salvage chemotherapy consisting of fludarabine, cytarabine, and G-CSF (FLAG) (or 5 day decitabine as an acceptable alternative) to be started 2 to 4 weeks prior to the CIML NK cell infusion, with Day -1 the day of T cell DLI, and Day 0 denoting the CIML NK cell infusion day. The donor will undergo non-mobilized large volume (20L) leukapheresis on Day -2 or -1, anticipating processing for T cell DLI and NK cell isolation on Day -1.
  • A second cycle of therapy may be administered if the patient shows evidence of AML > 30 days after the administration of the first course of protocol therapy, and if they continue to meet the inclusion/exclusion criteria. Salvage 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
-Day 0

Procedure: CD3+ T Cell Product Infusion
-Day -1




Primary Outcome Measures :
  1. 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) [ Time Frame: Completion of all patients through Day 0 (estimated to be 54 months) ]
    -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).

  2. Safety of administering CIML NK cells plus T cell DLT as measured by unexpected early mortality (Pilot Pediatric/Young Adult Cohort) [ Time Frame: Up to Day 100 ]
    • 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%.

  3. Safety of administering CIML NK cells plus T cell DLT as measured by unacceptable GVHD (Pilot Pediatric/Young Adult Cohort) [ Time Frame: Up to 12 months ]
    -The expected rate of GVHD is 20% and the maximum allowable rate is 45%.

  4. Safety of administering CIML NK cells plus T cell DLT as measured by prolonged neutropenia (Pilot Pediatric/Young Adult Cohort) [ Time Frame: 8 weeks post CIML NK infusion ]
    -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.

  5. Safety of administering CIML NK cells plus T cell DLT as measured by unexpected early mortality (Phase 2 Adult Cohort) [ Time Frame: Up to Day 100 ]
    • 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%.

  6. Safety of administering CIML NK cells plus T cell DLT as measured by unacceptable GVHD (Phase 2 Adult Cohort) [ Time Frame: Up to 12 months ]
    -The expected rate of GVHD is 20% and the maximum allowable rate is 45%.

  7. Safety of administering CIML NK cells plus T cell DLT as measured by prolonged neutropenia (Phase 2 Adult Cohort) [ Time Frame: 8 weeks post CIML NK infusion ]
    -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. Rate of leukemia-free survival (LFS) (Phase 2 Adult Cohort) [ Time Frame: 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 Outcome Measures :
  1. Complete remission rate (CR/CRi) (Pilot Pediatric/Young Adult Cohort) [ Time Frame: 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.

  2. Rate of leukemia-free survival (LFS) (Pilot Pediatric/Young Adult Cohort) [ Time Frame: 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.

  3. Overall survival (OS) (Pilot Pediatric/Young Adult Cohort) [ Time Frame: 100 days post CIML NK cell infusion ]
    -OS is defined as the time from the date of Day 0 until death from any cause.

  4. Rate of leukemia-free survival (LFS) (Pilot Pediatric/Young Adult Cohort) [ Time Frame: 1 year 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.

  5. Overall survival (OS) (Pilot Pediatric/Young Adult Cohort) [ Time Frame: 1 year post CIML NK cell infusion ]
    -OS is defined as the time from the date of Day 0 until death from any cause.

  6. Incidence and severity of acute GVHD rates (Pilot Pediatric/Young Adult Cohort) [ Time Frame: 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).

  7. Incidence and severity of acute GVHD rates (Pilot Pediatric/Young Adult Cohort) [ Time Frame: 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).

  8. Incidence and severity of chronic GVHD rates (Pilot Pediatric/Young Adult Cohort) [ Time Frame: 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).

  9. Complete remission rate (CR/CRi) (Phase 2 Adult Cohort) [ Time Frame: 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.

  10. Rate of leukemia-free survival (LFS) (Phase 2 Adult Cohort) [ Time Frame: 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.

  11. Overall survival (OS) (Phase 2 Adult Cohort) [ Time Frame: 100 days post CIML NK cell infusion ]
    -OS is defined as the time from the date of Day 0 until death from any cause.

  12. Rate of leukemia-free survival (LFS) (Phase 2 Adult Cohort) [ Time Frame: 1 year 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.

  13. Overall survival (OS) (Phase 2 Adult Cohort) [ Time Frame: 1 year post CIML NK cell infusion ]
    -OS is defined as the time from the date of Day 0 until death from any cause.

  14. Incidence and severity of acute GVHD rates (Phase 2 Adult Cohort) [ Time Frame: 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).

  15. Incidence and severity of chronic GVHD rates (Phase 2 Adult Cohort) [ Time Frame: 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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Recipient Inclusion Criteria:

  • Relapsed AML after HLA-matched related or unrelated allogeneic hematopoietic cell transplant (per IWG definition of relapse)
  • 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 >30,000/uL by morphology or flow cytometry (cyto-reductive therapies including leukapheresis or hydroxyurea are allowed).
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03068819


Contacts
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Contact: Amanda Cashen, M.D. 314-454-8323 acashen@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Amanda Cashen, M.D.    314-454-8323    acashen@wustl.edu   
Principal Investigator: Amanda Cashen, M.D.         
Sub-Investigator: Jeffrey Bednarski, M.D., Ph.D.         
Sub-Investigator: Todd Fehniger, M.D., Ph.D.         
Sub-Investigator: Shalini Shenoy, M.D.         
Sub-Investigator: Robert Hayashi, M.D.         
Sub-Investigator: Andrew Cluster, M.D.         
Sub-Investigator: John DiPersio, M.D., Ph.D.         
Sub-Investigator: Peter Westervelt, M.D., Ph.D.         
Sub-Investigator: Geoffrey Uy, M.D.         
Sub-Investigator: Ravi Vij, M.D.         
Sub-Investigator: Camille Abboud, M.D.         
Sub-Investigator: Rizwan Romee, M.D.         
Sub-Investigator: Meagan Jacoby, M.D., Ph.D.         
Sub-Investigator: Iskra Pusic, M.D.         
Sub-Investigator: Armin Ghobadi, M.D.         
Sub-Investigator: Mark Schroeder, M.D.         
Sub-Investigator: Keith Stockerl-Goldstein, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Amanda Cashen, M.D. Washington University School of Medicine
Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03068819    
Other Study ID Numbers: 201709041
First Posted: March 3, 2017    Key Record Dates
Last Update Posted: December 17, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No