Myelodysplastic Syndromes, Refractory Acute Myeloid Leukemia, Relapsed Acute Myeloid Leukemia
Conditions
Brief summary
Patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) will receive lymphodepleting chemotherapy (Flu/Cy) and two infusions of cytokine-induced memory-like NK cells at the previously defined maximum tolerated dose (MTD), fourteen days apart. Low dose rhIL-2 will be administered to patients for in vivo expansion following cell infusion. Patients will be assessed for anti-leukemic efficacy and safety. Re-infusion of patients who relapsed after clinical response will be considered.
Interventions
BIOLOGICALCytokine-induced memory-like NK cells
Cell product processing is performed at the Siteman Cancer Center Biological Therapy Core or another FACT-accredited cellular therapy production facility that can manufacture the product per the IND CMC.
DRUGFludarabine
-Lymphodepleting regimen
DRUGCyclophosphamide
-Lymphodepleting regimen
PROCEDUREDonor Leukapheresis
-Apheresis will be performed via peripheral IVs or central line, as determined by the apheresis team.
DRUGInterleukin-2
-IL-2 will start approximately 2-4 hours after the NK cell infusions.
Sponsors
Wugen, Inc.
Washington University School of Medicine
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
* Refractory AML without CR after induction therapy (primary induction failure); relapsed AML after obtaining a CR; progressive AML after non-intensive therapy (e.g., HMA + venetoclax or targeted therapy); Intermediate risk to very-high-risk MDS by IPSS-R that is relapsed or refractory after prior therapy with an HMA-containing regimen * At least 18 years of age. * Available allogeneic donor that meets the following criteria: * Able and willing to undergo multiple rounds of leukapheresis * At least 18 years of age * In general good health, and medically able to tolerate leukapheresis required for harvesting the NK cells for this study. * Negative for hepatitis, HTLV, and HIV on donor viral screen * Not pregnant * Voluntary written consent to participate in this study * All HLA-match/mismatch statuses will be included, with preference for unmatched donors all else being equal * Patients with known CNS involvement with AML are eligible provided that they have been treated and 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/Lansky performance status \> 50 % * Adequate organ function as defined below: * Total bilirubin \< 2 mg/dL * AST(SGOT)/ALT(SGPT) \< 3.0 x ULN * Creatinine within normal institutional limits OR creatinine clearance ≥ 40 mL/min by Cockcroft-Gault Formula * Oxygen saturation ≥90% on room air * Ejection fraction ≥35% * Able to be off corticosteroids and any other immune suppressive medications beginning on Day -3 and continuing until 30 days after the last infusion of the NK cell product. However, use of low-level corticosteroids is permitted if deemed medically necessary. Low-level corticosteroid use is defined as 10mg or less of prednisone (or equivalent for other steroids) per day. * 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 and until 30 days after the last NK cell product infusion. * Ability to understand and willingness to sign an IRB approved written informed consent document
Exclusion criteria
* Relapsed after allogeneic transplantation. * Circulating blast count \>30,000/µL by morphology or flow cytometry (cytoreductive therapies including leukapheresis or hydroxyurea are allowed). * Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B or C infection. * Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive of acute ischemia or active conduction system abnormalities. * New progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that have not been evaluated with bronchoscopy. Infiltrates attributed to infection must be stable/ improving after 1 week of appropriate therapy (4 weeks for presumed or proven fungal infections). * Known hypersensitivity to one or more of the study agents. * Received any investigational drugs within the 14 days prior to the first dose of fludarabine. * Pregnant and/or breastfeeding. * Any condition that, in the opinion of the investigator, would prevent the participant from consenting to or participating in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) of recipients | Through 12 month follow-up | * Defined as the proportion of patients achieving complete remission (CR), complete remission with partial hematologic recovery (CRh), and complete remission with incomplete blood count recovery (CRi). * Response will be assessed according to the criteria from the International Working Group Response Criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) of recipients | Through completion of follow-up (estimated to be 12 months) | -Defined as time from first dose of lymphodepleting chemotherapy (LDC) until death from any cause |
| Event free survival (EFS) of recipients | Through completion of follow-up (estimated to be 12 months) | -Defined as time from first dose of lymphodepleting chemotherapy (LDC) until treatment failure, relapse from complete response, or death |
| Duration of overall response (DOR) of recipients | Through 12 month follow-up | -Defined as duration for first occurrence of documented ORR until disease progression or death |
| Proportion of recipients that receive multiple doses of NK cell product | Through Day +14 of all recipients enrolled (estimated to be 19 months) | — |
| Number of dose-limiting toxicities (DLTs) that recipients experience in the safety lead-in cohort | Through Day 28 | — |
| Duration of complete response (DoCR) of recipients | Through 12 month follow-up | -Defined as duration from documented complete remission until disease progression or death |
| Number of adverse events experienced by recipients | Through Day +100 | * Incidence, nature, and severity of adverse events * Adverse events will be collected from Day 0 to Day +35; however, bone marrow suppression (ANC \< 500/µL) and adverse events of graft-versus-host disease (GVHD) involving the liver, skin, or gastrointestinal tract will be recorded until Day +100. |
| Proportion of recipients with prolonged cytopenia | At 8 weeks | — |
| Change in quality of life experienced by recipients as measured by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) | Day 0, Day +28, Day +100, 6 months, 9 months, and 12 months | — |
| Overall response rate (ORR) of recipients compared across subgroups | Through 12 month follow-up | * Subgroups will be defined by degree of HLA-match from allogeneic donor * Defined as the proportion of patients achieving complete remission (CR), complete remission with partial hematologic recovery (CRh), and complete remission with incomplete blood count recovery (CRi). * Response will be assessed according to the criteria from the International Working Group Response Criteria |
| Number of adverse events experienced by recipients compared across subgroups | Through Day +100 | * Subgroups will be defined by degree of HLA-match from allogeneic donor * Incidence, nature, and severity of adverse events * Adverse events will be collected from Day 0 to Day +35; however, bone marrow suppression (ANC \< 500/µL) and adverse events of graft-versus-host disease (GVHD) involving the liver, skin, or gastrointestinal tract will be recorded until Day +100. |
| Mortality rate of recipients | Day +30 | — |
Outcome results
None listed