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Patients with chemotherapy refractory Acute Myelogenous Leukemia (AML) after a double T-cell depleted (TCD) umbilical cord blood (UCB) transplantation where the smaller unit is activated overnight in interleukin-2 (IL-2). IL-2 will be given three times weekly for 6 doses beginning on days+3 and days +60 to expand UCB-derived natural killer (NK) cells in vivo.

On Day 8 pre-transplant, start hydration with allopurinol per standard of care.

On Days 7, 6 and 5 pre-transplant, 25 mg/m\^2 intravenously over 1 hour.

On Days 5, 4, 3, and 2 pre-transplant, 165 cGy times 2 (330 cGy daily, 1320 total dose) according to the University Of Minnesota Blood and Marrow Transplant Program total body irradiation (TBI) guidelines.

Total body irradiation

On Days 7 and 6 pre-transplant, 60 mg/kg intravenously (IV) over 2 hours with a high volume fluid flush and mesna per institutional guidelines.

Alternate Preparative Therapy For Patients Not Able To Receive TBI: Days 5, 4, 3 and 2 pre-transplant; 50 mg/kg/day IV over 2 hours.

Alternate Preparative Therapy for Patients Not Able to Receive Total Body Irradiation (TBI): Hydration therapy on Day 10 pre-transplant.

Alternate Preparative Therapy For Patients Not Able To Receive TBI: Days 9, 8, 7 and 6 pre-transplant; 0.8 mg/kg (1.1 mg/kg if \<12 kg) intravenously every 6 hours

Day 0: Two UCB units will compose the graft. The infusion of the first UCB unit should begin within 15 minutes, and no later than 30 minutes after arrival on the Unit. The UCB unit without IL-2 activation will be infused first, followed by the IL-2 activated unit. Both cords will be infused within 30-60 minutes of each other as deemed clinically safe by the BMT attending.

Umbilical Cord Blood Transplantation

First Course of IL-2 (begin day +3) post-transplant: For patients ≥ 45 kg, IL-2 will be given at 9 million units every other day for a total of 6 doses subcutaneously. Patients weighing less than 45 kilograms, the IL-2 will be dosed at 5 million units/m\^2 every other day for a total of 6 doses.

Second Course of IL-2 (day +60):

Patients will receive a second course of IL-2 beginning on Day +60 post transplant to expand and educate the NK cells derived from the UCB graft source.

Michael Verneris, M.D.

This trial is proposes to build on our experience and is designed to maximize early (day 3-14) and late (day 60-71) donor-derived natural killer (NK) cell expansion and function in vivo. The proposed platform will allow us the unique opportunity to compare in vivo function from a transplanted umbilical cord blood (UCB) source (presumed to contain NK progenitors requiring "education" in the recipient).

This single center study will determine the feasibility and safety of using a myeloablative conditioning regimen followed (on day 0) by transplantation with double T-cell depleted (TCD) umbilical cord blood (UCB) units where the unit with fewer mononuclear cells (MNCs)/kg will be selected for overnight IL-2 activation prior to infusion. Beginning on day +3, post transplant IL-2 will be administered thrice weekly, not on consecutive days, for a total of 6 doses to expand UCB derived progenitor cells. Post transplant immune suppression prophylaxis will not be administered with the intent to lessen toxicity and allow allogeneic NK cells to function longer providing better anti-leukemic therapy. However if either UCB unit has more than 5% T-cells, the patient will not receive either course of IL-2. Beginning on day +60 after transplantation, a second course of IL-2 will be administered thrice weekly, not on consecutive days, for a total of 6 doses with the purpose of enhancing the in vivo expansion and education of NK cells derived from engrafting UCB cells.

T-Cell Depleted Double UCB for Refractory AML

T-Cell Depleted Double UCB With Post Transplant IL-2 for Refractory Myeloid Leukemia

The primary endpoint is a disease free survival at 3 months in patients with chemotherapy refractory AML after a double T-cell depleted (TCD) umbilical cord blood (UCB) transplantation where one TCD unit is activated overnight in IL-2 followed by the administration of two courses of IL-2 three times a week for 6 doses beginning on day +3 and on day +60 to expand UCB-derived NK cells in vivo.

Incidence of graft failure defined as an absolute neutrophil count of less than 500/uL and a bone marrow that is less than 5% cellular (marrow aplasia)

Defined as leukemia clearance and complete remission. Patients will be followed for disease response for 1 year from transplantation unless: consent is withdrawal, patient is unevaluable - if a patient is not evaluable, follow only until the resolution or stabilization of treatment related toxicity, new anti-cancer treatment is started, patient is discharged to hospice (terminal) care.

Defined as leukemia clearance and complete remission. Patients will be followed for disease response for 2 years from transplantation unless: consent is withdrawal, patient is unevaluable - if a patient is not evaluable, follow only untilthe resolution or stabilization of treatment related toxicity, new anti-cancer treatment is started, patient is discharged to hospice (terminal) care.

Masonic Cancer Center, University of Minnesota

Allopurinol: start on Day -8 per institutional guidelines Fludarabine: give on Days -7, -6 and -5, 25 mg/m\^2 intravenously (IV) Cyclophosphamide: give on Days -7 and -6, 60 mg/kg IV along with mesna per institutional guidelines Total body irradiation: give on Days -5, -4, -3, and -2, 165 cGy twice daily Double T-cell depleted umbilical cord blood transplantation with activation of one of the units in interleukin-2 (IL-2): give on Day 0 IL-2: start on Day +3 and Day +60, 9 MU subcutaneously three times weekly for 6 doses

Alternate preparative therapy for patients not able to receive additional radiation

Levetiracetam (Keppra): begin on Day -10 per institutional guidelines Busulfan: give Day -9 through Day -6, 0.8 mg/kg (1.1 mg/kg if \<12 kg) IV every 6 hours Cyclophosphamide: give Day -5 through Day -2, 50 mg/kg/day IV along with mesna per institutional guidelines

Patients With Acute Myelogenous Leukemia

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

Michael R Verneris

Disease Free Survival

Incidence of Graft Failure

Incidence of Acute Graft-Versus-Host Disease

Transplant-Related Mortality

Clinical Disease Response

Duration of Survival

Overall Study

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.

FATE-NK100

Murali Janakiram, MD, MS

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.

Open Label NK Cell Infusion (FATE-NK100) With Subq IL-2 in Adults With AML

Open Label Dose Escalation Trial of an Adaptive Natural Killer (NK) Cell Infusion (FATE-NK100) With Subcutaneous IL-2 in Adults With Refractory or Relapsed Acute Myelogenous Leukemia (AML)

Maximum FATE-NK100 dose which could be given to 3 participants such that not more than 1 participant experienced a DLT.

Incidence of CRp defined as leukemia clearance (≤5%marrow blasts and no circulating peripheral blasts)

Incidence of CRp defined as neutrophil recovery (ANC \>500 cells/microliter) but with incomplete platelet recovery

Incidence of in vivo expansion (≥ 100 donor derived NK cells per uL blood) of NK cells

Incidence of treatment related mortality (TRM)

Incidence of minimal residual disease (MRD) clearance by bone marrow morphology after NK Cell infusion

Incidence of minimal residual disease (MRD) clearance by flow cytometry after NK Cell infusion

Incidence of Leukemia free survival (LFS)

Immune System Diseases

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Lymphosarcoma

Nine pre-defined dose levels for specific subsets of subjects will be administered by IV (in the vein). PR104 will be administered initially as induction therapy followed by administration as consolidation therapy, as is typical of established treatment regimens in AML.

PR104

The current understanding of PR104 justifies the evaluation of PR104 in subjects with relapsed/refractory AML and ALL. These include:

* Hypoxia. Leukemic bone marrow is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M.
* Myelotoxicity as the primary toxicity at MTD. In prior clinical studies in subjects with solid tumors PR104 has demonstrated myelotoxicity as the primary toxicity. This observation suggests that PR104 will exert a similar effect on leukemic cells.
* AKR1C3. AML has been reported to exhibit high levels of AKR1C3 which should lead to selective activation of PR104 within both hypoxic and oxic leukemic cells.
* Preclinical data. PR104 has demonstrated impressive activity in an initial study using primary human ALL in a mouse model.

The initial dose finding phase of the study will provide estimates of the activity and toxicity of PR104 in subjects with refractory/relapsed AML, and determine the optimal individualized dose to give each subject based on his/her covariates (prior CR duration, prior number of salvage therapies, age). Once a potentially beneficial dose has been determined, an expanded cohort of subjects with AML or ALL will receive PR104 at a uniform dose. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity and acceptable safety in AML to warrant future phase II or phase III studies in this indication.

Primary objectives

* Determine the toxicities and recommended dose of PR104 when administered IV to subjects with relapsed/refractory AML and ALL.

Secondary objectives

* Evaluate the pharmacokinetics (PK) of PR104 and a series of PR104 metabolites
* Evaluate any anti-tumor effects of PR104
* Evaluate the expression of AKR1C3 in bone marrow and leukemic cells
* Evaluate potential biomarkers of hypoxia

A single arm study defining the recommended dose of PR104 for each subpopulation in this patient population.

Following informed consent, subjects will undergo baseline evaluation with a history, physical exams, blood work, and disease assessment. Subjects will be assigned a dose of PR104 based on a Bayesian model maintained at the Statistical department at MD Anderson Cancer Center. The model will be updated with both toxicity and efficacy data as it is generated for each subject. New subjects will receive the currently predicted best dose for their respective subset based on prior treatment, age and duration of prior response.

PR104 will be administered initially as induction therapy for up to 3 cycles. Response will be assessed around day 42 (+/- 2 days) of the study. Subjects who obtain a CR or CRp will receive consolidation therapy for up to 4 additional cycles.

Subjects will be evaluated each week during the induction phase of the study. During the consolidation phase of the study, subjects will be evaluated on Day 1 of each cycle and as clinically indicated. Subjects with clinically significant progression will be removed from study.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
T-Cell Depleted Double UCB for Refractory AML	NCT01464359	Acute Myelogeno... Refractory Acut...	Allopurinol Fludarabine Total body irra... Cyclophosphamid... Levetiracetam Busulfan Umbilical Cord ... Interleukin-2	2 Years - 45 Years	Masonic Cancer Center, University of Minnesota
Open Label NK Cell Infusion (FATE-NK100) With Subq IL-2 in Adults With AML	NCT03081780	Refractory Acut... Relapsed Acute ...	FATE-NK100	18 Years - 70 Years	Masonic Cancer Center, University of Minnesota
Open Label NK Cell Infusion (FATE-NK100) With Subq IL-2 in Adults With AML	NCT03081780	Refractory Acut... Relapsed Acute ...	FATE-NK100	18 Years - 70 Years	Masonic Cancer Center, University of Minnesota
PR104 in Treating Patients With Refractory/Relapsed Acute Leukemia	NCT01037556	Acute Myelogeno... Acute Lymphocyt...	PR104	18 Years -	Proacta, Incorporated

Spots Global Cancer Trial Database for refractory acute myelogenous leukemia