Adapt NK for High Risk Myeloid Diseases as Bridge to Allo HSCT

Purpose

This is a multi-institutional Phase I/II study of an allogeneic KIR-HLA mismatched NK cell infusion (AdaptNK) and a short course of subcutaneous interleukin-2 (IL-2) administered after lymphodepleting chemotherapy [cyclophosphamide (CY)/fludarabine (FLU)] in patients with relapsed or refractory acute myelogenous leukemia (AML). AdaptNK is a natural killer (NK) cell product that is enriched for NK cells with an "adaptive", or human cytomegalovirus (CMV)-induced, phenotype.

Conditions

  • Relapsed Adult AML
  • Refractory AML
  • Acute Myelogenous Leukemia

Eligibility

Eligible Ages
Over 18 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • 18-74 years with Karnofsky score ≥ 70% - 75 years and older: KPS ≥ 70%, HCT-CI < 5 (excluding history of solid tumor), AND not frail by Fried frailty criteria (see Appendix III) - HLA type C1/C1 or C2/C2 Note: For easy determination, the definition of HLA-C ligand group assigments is included below: HLA-C1 group alleles are defined as HLA-C01, C03, C07, C08, C12, C14, C16 HLA-C2 group alleles are defined as HLA-C02, C04, C05, C06, C15, C17, C18 - adequate liver, renal, pulmonary and cardiac function - ability to be off glucocorticoids and other immunosuppressive medications indicated for acute or chronic GVHD for at least 28 days prior to the AdaptNK cell infusion - There must be sufficient time between the most recent therapy and the screening bone marrow as delineated below: - anti-leukemic systemic cytotoxic chemotherapy - 2 weeks - Targeted anti-leukemic agents (FLT-3, IDH, menin inhibitors) - 3 half-lives of the medication - Radiotherapy - 1 week - donor lymphocyte infusions - 6 weeks - hematopoietic growth factors (filgrastim, TPO agonists, EPO) - 1 week - biologic therapy (monoclonal antibodies, T-cell engagers) - 2 weeks - Immune effector cellular therapy - 4 weeks - Intrathecal chemotherapy for treatment of active CNS leukemia - there must be at least two CSF samples negative for leukemia separated by one week before enrollment. - WBC shall be < 25,000 before infusion. Hydroxyurea is permitted until day -3 to control excess blast proliferation. No other systemic treatment is allowed after the screening bone marrow is performed for inclusion in protocol - All prior treatment related toxicities should have resolved to ≤ grade 1 prior to study enrollment - agrees to use of adequate contraception from study enrollment to 4 months after cell infusion - voluntary written consent

Exclusion Criteria

  • Myeloid neoplasms with known or strongly suspected germline background, except DDX41, TP53, or RUNX1. - Acute promyelocytic leukemia (APL) - myocardial infarction (MI) within previous 6 months of study enrollment - pregnant or breastfeeding - Active CNS involvement with AML - new or progressive pulmonary infiltrates - active autoimmune disease requiring immunosuppressive therapy - Preexisting inflammatory disease requiring immunosuppressive therapy - history of severe asthma and currently on chronic systemic medications - HIV-1/2 positivity or hepatitis C/B - active systemic infections requiring anti-infective treatment - received any investigational agent within the 14 days before the start of study treatment (1st dose of fludarabine) - Patients with second malignancies are excluded if they have required systemic cytotoxic chemotherapy within 1 year or if they are not in remission - Exception: patients that are on stable dosing of hormonal therapy (e.g. aromatase inhibitor or antiandrogen therapy) for active breast or prostate cancer for 1 year are eligible. - Patients with excised basal cell or squamous cell carcinoma of the skin are eligible. - Patients with excised carcinoma in situ of the cervix or breast are eligible. - Patients with untreated T1a or T1b prostate cancer are eligible.

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Sequential Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Dose Level Cohort -1 		Safety dose level. < 1 x 10^8 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
  • Biological: AdaptNK
    The NK cell product is comprised of peripheral blood (PB) leukocytes sourced from a cryopreserved pool. of third-party donors that are seropositive for cytomegalovirus (CMV+), have NK cells expressing >20% NKG2C and >30% single-self KIR and depleted from CD3+ (T-lymphocytes) and CD19+ (B-lymphocytes) cells.
  • Drug: Fludarabine
    25 mg/kg administered on days -6, -5, -4, -3 and -2. Part of Lymphodepleting conditioning chemotherapy regimen.
  • Drug: Cyclophosphamide
    60 mg/kg administered on days -5 and -4. Part of Lymphodepleting conditioning chemotherapy regimen.
  • Drug: IL-2
    IL-2 at 6 million IU subcutaneously (SC) every other day (EOD) for 3 doses with Dose 1 on Day 0 (no sooner than 4 hours post cell infusion) with the last dose no later than Day +8.
Experimental
Dose Level Cohort 1 		2.4 - 3 x 10^8 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
  • Biological: AdaptNK
    The NK cell product is comprised of peripheral blood (PB) leukocytes sourced from a cryopreserved pool. of third-party donors that are seropositive for cytomegalovirus (CMV+), have NK cells expressing >20% NKG2C and >30% single-self KIR and depleted from CD3+ (T-lymphocytes) and CD19+ (B-lymphocytes) cells.
  • Drug: Fludarabine
    25 mg/kg administered on days -6, -5, -4, -3 and -2. Part of Lymphodepleting conditioning chemotherapy regimen.
  • Drug: Cyclophosphamide
    60 mg/kg administered on days -5 and -4. Part of Lymphodepleting conditioning chemotherapy regimen.
  • Drug: IL-2
    IL-2 at 6 million IU subcutaneously (SC) every other day (EOD) for 3 doses with Dose 1 on Day 0 (no sooner than 4 hours post cell infusion) with the last dose no later than Day +8.
Experimental
Dose Level Cohort 2 		0.8 - 1 x 10^9 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
  • Biological: AdaptNK
    The NK cell product is comprised of peripheral blood (PB) leukocytes sourced from a cryopreserved pool. of third-party donors that are seropositive for cytomegalovirus (CMV+), have NK cells expressing >20% NKG2C and >30% single-self KIR and depleted from CD3+ (T-lymphocytes) and CD19+ (B-lymphocytes) cells.
  • Drug: Fludarabine
    25 mg/kg administered on days -6, -5, -4, -3 and -2. Part of Lymphodepleting conditioning chemotherapy regimen.
  • Drug: Cyclophosphamide
    60 mg/kg administered on days -5 and -4. Part of Lymphodepleting conditioning chemotherapy regimen.
  • Drug: IL-2
    IL-2 at 6 million IU subcutaneously (SC) every other day (EOD) for 3 doses with Dose 1 on Day 0 (no sooner than 4 hours post cell infusion) with the last dose no later than Day +8.
Experimental
Dose Level Cohort 3 		2.4 - 3 x 10^9 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
  • Biological: AdaptNK
    The NK cell product is comprised of peripheral blood (PB) leukocytes sourced from a cryopreserved pool. of third-party donors that are seropositive for cytomegalovirus (CMV+), have NK cells expressing >20% NKG2C and >30% single-self KIR and depleted from CD3+ (T-lymphocytes) and CD19+ (B-lymphocytes) cells.
  • Drug: Fludarabine
    25 mg/kg administered on days -6, -5, -4, -3 and -2. Part of Lymphodepleting conditioning chemotherapy regimen.
  • Drug: Cyclophosphamide
    60 mg/kg administered on days -5 and -4. Part of Lymphodepleting conditioning chemotherapy regimen.
  • Drug: IL-2
    IL-2 at 6 million IU subcutaneously (SC) every other day (EOD) for 3 doses with Dose 1 on Day 0 (no sooner than 4 hours post cell infusion) with the last dose no later than Day +8.

Recruiting Locations

Mark Juckett, MD
Minneapolis, Minnesota 55455
Contact:
Mark Juckett, MD
612-676-4200
juck0001@umn.edu

More Details

Status
Recruiting
Sponsor
Masonic Cancer Center, University of Minnesota

Study Contact