Refractory Acute Myelogenous Leukemia, Relapsed Acute Myelogenous Leukemia
Conditions
Keywords
AML
Brief summary
This is a Phase I open-label dose escalation study of a single infusion of FATE-NK100 and a short course of subcutaneous interleukin-2 (IL-2) administered after lymphodepleting chemotherapy (CY/FLU) in subjects with refractory or relapsed acute myelogenous leukemia (AML). FATE-NK100 is a natural killer (NK) cell product that is enriched for NK cells with an adaptive, or human cytomegalovirus (CMV)-induced, phenotype. The NK cell product is comprised of peripheral blood (PB) leukocytes sourced from a related donor (HLA-haploidentical or better but not fully HLA-matched) that is seropositive for cytomegalovirus (CMV+), and enriched for adaptive NK cells by depletion of CD3+ (T-lymphocytes) and CD19+ (B-lymphocytes) cells followed by ex-vivo culture expansion.
Interventions
BIOLOGICALFATE-NK100
Preparative regimen: * Fludarabine 25 mg/m2 x 5 days start Day -6 * Cyclophosphamide 60 mg/kg x 2 days on Day -5 and -4 Apheresis cell collection (collected from the Donor Day - 8) will be enriched for FATE-NK100 per CMC. IL-2 at 6 million IU subcutaneously (SC) every other day (EOD) for 6 doses with Dose 1 on Day 0 (no sooner than 4 hours post NK cells) and last dose no later than Day +12.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
\- ≥18 but ≤ 70 years of age * Diagnosis of acute myeloid leukemia (AML) and meets one of the following disease criteria: \* Primary induction failure: \*\* De Novo AML: no CR after 2, 3 or 4 induction attempts with high dose chemotherapy * Secondary AML (from MDS or treatment related): no CR after 1, 2 or 3 cycles of high dose chemotherapy * Relapsed: * Not in CR after 1 or 2 cycles of standard re-induction therapy * Relapse diagnosed at the time of the 6 months post-HCT standard of care follow-up or later (i.e. based on bone marrow biopsy performed Day +170 or later) and without evidence of graft versus host disease (GVHD) * For patients \> 60 years of age, the minimum of 1 cycle of standard chemotherapy is not required. * Available HLA-matched or better but not fully HLA-matched (2/4 or 3/4 antigens) related donor (aged 18 to 75 years) with donor/recipient match based on a minimum of intermediate resolution DNA based Class I typing of the A and B locus who is CMV seropositive. * Karnofsky Performance Status ≥ 60% * Adequate organ function within 14 days of study registration (28 days for pulmonary and cardiac) defined as: * Creatinine: Estimated glomerular filtration rate (eGFR) ≥ 50 mL/min/1.73m\^2 per current institutional calculation formula * Hepatic: AST and ALT ≤ 3 x upper limit of institutional normal * Pulmonary Function: oxygen saturation ≥ 90% on room air; PFT's required only if symptomatic or prior known impairment - must have pulmonary function \>50% corrected DLCO and FEV1 * Cardiac Function: LVEF ≥ 40% by echocardiography or MUGA * No symptomatic active conduction system abnormalities * Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to FATE-NK100 cell infusion (excluding preparative regimen premedications) * Sexually active females of child bearing potential and males with partners of child bearing potential must agree to use effective contraception during therapy and for 4 months after completion of therapy * Voluntary written consent prior to the performance of any research related procedures Arm Specific Inclusion Criteria High-Risk aGVHD (ARM 1): \- Pediatric or adult (ages 0-76 years) HCT recipients with high-risk acute GVHD, as determined either by the refined MN acute GVHD risk score \[28\]: http://z.umn.edu/MNAcuteGVHDRiskScore OR high risk on the basis of blood biomarkers (Ann Arbor Score 3) \[31\]. Patients in this arm must start treatment within the first 7 days after onset of high-risk aGVHD. or Steroid- Dependent aGVHD (ARM 2A): \- Pediatric or adult (ages 0-76 years) HCT recipient with grade II-IV steroid-dependent acute GVHD, defined as any one of the following: Flare of acute GVHD of at least grade II/IV severity within 8 weeks of tapering down or (off of) immunosuppression for acute GVHD, with the flare occurring on ≤0.5 mg/kg prednisone. This can include late-onset aGVHD and overlap syndrome. or Steroid-Refractory aGVHD (ARM 2B): \- Pediatric or adult (ages 0-76 years) HCT recipient with grade II-IV steroid refractory acute GVHD, defined as any one of the following: * No response of acute GVHD after at least 4 days of systemic corticosteroids of at least 2 mg/kg prednisone or equivalent * Progression of acute GVHD within 3 days of systemic corticosteroids of at least 2 mg/kg prednisone or equivalent * Failure to improve to at least grade II acute GVHD after 14 days of systemic corticosteroids, with initial doses of at least 2 mg/kg prednisone or equivalent * Flare of acute GVHD of at least grade II/IV severity while on steroids at a dose \>0.5/mg/kg/day. This can include late-onset aGVHD and overlap syndrome.
Exclusion criteria
* Myocardial Infraction (MI) within the previous 6 months * Acute leukemias of ambiguous lineage * Pregnant or breastfeeding - The agents used in this study include those that fall under Pregnancy Category D - have known teratogenic potential. Women of child bearing potential must have a negative pregnancy test at screening * History of or known active CNS involvement with AML * Active autoimmune disease requiring systemic immunosuppressive therapy * History of severe asthma and currently on chronic systemic medications (mild asthma requiring inhaled steroids only is eligible) * New or progressive pulmonary infiltrates on screening chest X-ray or chest CT scan unless cleared for study by Pulmonary. Infiltrates attributed to infection must be stable/improving (with associated clinical improvement) after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections). * Uncontrolled bacterial, fungal or viral infections including HIV-1/2 or active hepatitis C/B - chronic asymptomatic viral hepatitis is allowed * Received any investigational agent within the 14 days before the start of study treatment (1st dose of fludarabine)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose (MTD) | 3 months | Maximum FATE-NK100 dose which could be given to 3 participants such that not more than 1 participant experienced a DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical activity by CR/CRp neutrophil recovery | Day +42 | Incidence of CRp defined as neutrophil recovery (ANC \>500 cells/microliter) but with incomplete platelet recovery |
| In vivo expansion of NK cells | Day +14 | Incidence of in vivo expansion (≥ 100 donor derived NK cells per uL blood) of NK cells |
| Treatment Related Mortality (TRM) | 6 months | Incidence of treatment related mortality (TRM) |
| Clinical activity by CR/CRp leukemia clearance | Day +42 | Incidence of CRp defined as leukemia clearance (≤5%marrow blasts and no circulating peripheral blasts) |
| Minimal residual disease (MRD) by flow cytometry | up to Day 28 | Incidence of minimal residual disease (MRD) clearance by flow cytometry after NK Cell infusion |
| Leukemia free survival (LFS) | 1 year | Incidence of Leukemia free survival (LFS) |
| Overall survival (OS) | 1 year | Incidence of overall survival (OS) |
| Minimal residual disease (MRD) by bone marrow morphology | up to Day 28 | Incidence of minimal residual disease (MRD) clearance by bone marrow morphology after NK Cell infusion |
Countries
United States
Outcome results
None listed