FATE-NK100 Donor Natural Killer Cells, Aldesleukin, and Combination Chemotherapy in Treating Patients with Refractory or Relapsed Acute Myeloid Leukemia

This phase I trial studies the side effects and best dose of FATE-NK100 donor natural killer (NK) cells when given together with aldesleukin and combination chemotherapy in treating patients with acute myeloid leukemia that does not respond to treatment or has come back. The FATE-NK100 NK cell product is made from white blood cells collected from a related donor who is has been exposed to cytomegalovirus (CMV). These “adaptive” NK cells may have more potent anti-cancer killing. Aldesleukin may help FATE-NK100 cells expand and survive in the blood and bone marrow. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving FATE-NK100 donor natural killer cells together with aldesleukin and combination chemotherapy may work better treating patients with acute myeloid leukemia.

Inclusion Criteria

• 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 myelodysplastic syndrome [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 *** For patients > 60 years of age, the minimum of 1 cycle of standard chemotherapy is not required ** Relapse diagnosed at the time of the 6 months post-hematopoietic cell transplantation (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) * Notes: ** For hypomethylating agents (i.e. decitabine, azacititdine) to count as an induction/re-induction attempt, the patient must have completed a minimum of 3 monthly cycles ** For targeting agents (i.e. sorafenib) to count as an induction/re-induction attempt, the patient must have completed a minimum of 1 month without attaining CR ** 7+3 followed by 5+2 counts as TWO induction attempts ** Use of hydroxyurea is permitted to control blasts until day -3
• Available human leukocyte antigen (HLA)-haploidentical 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 deoxyribonucleic acid (DNA) based class I typing of the A and B locus who is CMV seropositive
• Karnofsky Performance Status >= 60%
• Estimated glomerular filtration rate (eGFR) >= 50 mL/min/1.73m^2 per current institutional calculation formula (within 14 days of study registration)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of institutional normal (within 14 days of study registration)
• Oxygen saturation >= 90% on room air; pulmonary function tests (PFT’s) required only if symptomatic or prior known impairment - must have pulmonary function > 50% corrected diffusion capacity of the lung for carbon monoxide (DLCO) and forced expiratory volume in 1 second (FEV1) (within 28 days of study registration)
• Left ventricular ejection fraction (LVEF) >= 40% by echocardiography or multi-gated acquisition scan (MUGA) or cardiac magnetic resonance imaging (MRI) (within 28 days of study registration)
• No symptomatic active conduction system abnormalities (within 28 days of study registration)
• Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to FATE-NK100 cell infusion (excluding preparative regimen pre-medications)
• 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
• DONOR ELIGIBILITY REQUIREMENTS: HLA-haploidentical or better but not fully HLA-matched 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 (2/4 or 3/4 class I allele) (determined during pre-screening)
• DONOR ELIGIBILITY REQUIREMENTS: Seropositive for cytomegalovirus (CMV+) as determined during pre-screening
• DONOR ELIGIBILITY REQUIREMENTS: Body weight of at least 40 kilograms
• DONOR ELIGIBILITY REQUIREMENTS: In general good health as determined by the medical provider
• DONOR ELIGIBILITY REQUIREMENTS: Hemoglobin within 10% of upper and lower limit of normal range of test (gender based for hemoglobin)
• DONOR ELIGIBILITY REQUIREMENTS: White blood cell (WBC) within 10% of upper and lower limit of normal range of test
• DONOR ELIGIBILITY REQUIREMENTS: Platelet within 10% of upper and lower limit of normal range of test
• DONOR ELIGIBILITY REQUIREMENTS: Alanine aminotransferase (ALT) < 2 x upper limit of normal
• DONOR ELIGIBILITY REQUIREMENTS: Serum creatinine < 1.8 mg/dl
• DONOR ELIGIBILITY REQUIREMENTS: Performance of a donor infectious disease screen panel including CMV antibody, hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody, HIV 1/2 antibody, human T-lymphotropic virus antibody (HTLVA) 1/2 antibody, Treponema and Trypanosoma cruzi (T. cruzi) plus hepatitis B virus (HBV), hepatitis C virus (HCV), West Nile virus (WNV), HIV by nucleic acid method, and risk assessment for Zika virus exposure or per current standard institutional donor screen – must be negative for HIV and active hepatitis B
• DONOR ELIGIBILITY REQUIREMENTS: Not pregnant - females of childbearing potential must have a negative pregnancy test within 7 days of apheresis
• DONOR ELIGIBILITY REQUIREMENTS: Voluntary written consent prior to the performance of any research related procedure

Exclusion Criteria

• Myocardial Infraction (MI) within the previous 6 months
• Acute leukemias of ambiguous lineage
• Pregnant or breastfeeding; women of child bearing potential must have a negative pregnancy test at screening
• History of or known active central nervous system (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 computed tomography (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 human immunodeficiency virus (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 phosphate [fludarabine])

PRIMARY OBJECTIVES:

I. To assess the safety and determine the maximum tolerated dose (MTD) or maximum feasible dose (MFD) of allogeneic CD3- CD19- CD57+ NKG2C+ NK cells FATE-NK100 (FATE-NK100) administered intravenously (IV) in patients with refractory or relapsed acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. To assess clinical activity by complete remission/complete remission with incomplete platelet recovery (CR/CRp) at 42 days where CR is defined as =< 5% blasts in the bone marrow (BM), recovery of neutrophils and platelets, and the absence of extramedullary disease and CRp is defined as leukemia clearance (=< 5% marrow blasts and no circulating peripheral blasts) and neutrophil recovery but with incomplete platelet recovery.

II. To determine the incidence of in vivo expansion (>= 100 donor derived NK cells per uL blood) of NK cells by day +7 and day +14.

III. To evaluate the safety of FATE-NK100 as measured by rate of treatment related mortality (TRM) at 6 months.

IV. To evaluate the rate of minimal residual disease (MRD) clearance.

V. To measure leukemia free survival (LFS) and overall survival (OS) at 1 year.

CORRELATIVE OBJECTIVES:

I. To measure function of in vivo expanded adoptively transferred FATE-NK100.

II. To correlate CR/CRp with in vivo expansion of FATE-NK100.

OUTLINE: This is a dose-escalation study of FATE-NK100.

Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. Patients then receive FATE-NK100 IV over 15 minutes to 1 hour on day 0 and aldesleukin subcutaneously (SC) every other day (QOD) on days 0-10.

After completion of study treatment, patients are followed up at 2, 3, 6, and 12 months.

Lead Organization
University of Minnesota / Masonic Cancer Center

Principal Investigator
Murali Janakiram

Primary ID 2016LS153
Secondary IDs NCI-2017-01462
Clinicaltrials.gov ID NCT03081780