Acute Myelogenous Leukemia, Refractory AML, Relapsed Adult AML
Conditions
Brief summary
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.
Interventions
BIOLOGICALAdaptNK
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.
DRUGFludarabine
25 mg/kg administered on days -6, -5, -4, -3 and -2. Part of Lymphodepleting conditioning chemotherapy regimen.
DRUGCyclophosphamide
60 mg/kg administered on days -5 and -4. Part of Lymphodepleting conditioning chemotherapy regimen.
DRUGIL-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.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose (MTD) | 1 year | The primary objective of the study is to assess the safety and determine the maximum tolerated dose (MTD) of AdaptNK administered as a single infusion intravenously (IV) to KIR-HLA mismatched patients with relapsed or refractory AML. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response (OR) | Day 42 | includes complete remission with or without hematologic recovery (CR or CRi) or partial remission (PR) |
| Safety of AdaptNK | Day 42 | measured by rate of treatment related mortality (TRM) |
Countries
United States
Outcome results
None listed