T-Cell Depleted Double UCB for Refractory AML

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Acute Myelogenous Leukemia, Refractory Acute Myelogenous Leukemia

Intervention / Treatment
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* Drug: Allopurinol
* Drug: Fludarabine
* Radiation: Total body irradiation
* Drug: Cyclophosphamide
* Drug: Levetiracetam
* Drug: Busulfan
* Biological: Umbilical Cord Blood Transplantation
* Biological: Interleukin-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 2 to 45 years with acute myeloid leukemia (AML) who meet one of the following criteria: Primary induction failure defined as no complete remission (CR) after two or three induction cycles (no blast limit). Relapsed AML with low disease burden: For patients >21 through 45 years of age: must have <30% marrow blasts within 14 days of enrollment and be at least 28 days from the start of last therapy. For patients 2 through ≤ 21 years of age: must have >5% marrow blasts after no more than 3 induction attempts. Patients with prior central nervous system (CNS) involvement are eligible provided that it has been treated and is in remission. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the protocol. Have acceptable organ function within 14 days of study registration defined as: Renal: creatinine ≤ 2.0 mg/dL (adult patients) or calculated creatinine clearance > 40 ml/min (pediatric patients) Hepatic: bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) ≤ 5 times upper limit of normal Pulmonary function: diffusing lung capacity for carbon monoxide corrected for hemoglobin (DLCOcorr) > 50% of normal, (oxygen saturation [>92%] can be used in child where pulmonary function tests (PFT's) cannot be obtained) Cardiac: left ventricular ejection fraction ≥ 45% Karnofsky Performance Status ≥ 70% (≥ 16 years) or Lansky Play Score ≥ 50 (pediatrics < 16 years) Women of childbearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment. All patients will be questioned about prior exposure to antibody therapy (including OKT3, rituximab, trastuzumab, and gemtuzumab) without affect to eligibility. Patients with prior exposure will have a blood sample collected for human antimouse antibody (HAMA). For patients with no prior antibody therapy exposure, no further action will be taken. Voluntary written consent Exclusion Criteria: Active infection at time of enrollment or documented fungal infection within 3 months unless clearance from Infectious Disease Evidence of HIV infection or known HIV positive serology Pregnant or breast feeding. If < or = 21 years old, prior myeloablative transplant within the last 6 months. If > 21 years old prior myeloablative allotransplant or autologous transplant - if prior conditioning regimen included total body irradiation (TBI), then busulfan/cyclophosphamide(BU/CY) prep should be used If > 21 years old - extensive prior therapy including > 12 months of any alkylator chemotherapy (etoposide >100 mg/m^2 x 5 days, cyclophosphamide >1 gm/m^2 or mitoxantrone >8 gm/m^2) delivered at 3-4 week intervals or > 6 months alkylator therapy (as above) with extensive radiation (determined by Radiation Oncology, e.g. mantle irradiation for Hodgkin's) and/or prior radiation therapy that makes a patient ineligible for TBI. Known hypersensitivity to any of the study agents

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with Acute Myelogenous Leukemia<br>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. | Drug: Allopurinol<br>* On Day 8 pre-transplant, start hydration with allopurinol per standard of care.<br>* Other names: Zyloprim;Drug: Fludarabine<br>* On Days 7, 6 and 5 pre-transplant, 25 mg/m^2 intravenously over 1 hour.<br>* Other names: Fludara;Radiation: Total body irradiation<br>* 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.<br>* Other names: Radiation;Drug: Cyclophosphamide<br>* 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.<br>* Other names: Cytoxan;Drug: Levetiracetam<br>* Alternate Preparative Therapy for Patients Not Able to Receive Total Body Irradiation (TBI): Hydration therapy on Day 10 pre-transplant.<br>* Other names: Keppra;Drug: Busulfan<br>* 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<br>* Other names: Myleran;Biological: Umbilical Cord Blood Transplantation<br>* 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.<br>* Other names: UCBT;Biological: Interleukin-2<br>* 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.<br>* Other names: IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival | 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. | At 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Graft Failure | 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) | Day 42 | 
| Incidence of Acute Graft-Versus-Host Disease |  | Day 60 | 
| Transplant-Related Mortality |  | Day 180 after Transplantation | 
| Clinical Disease Response | 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. | 1 Year from Transplantation | 
| Duration of Survival |  | 6 months after Transplantation. | 
| Duration of Survival |  | 1 year after Transplantation. | 
| Duration of Survival |  | 2 years after Transplantation. | 
| Clinical Disease Response | 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. | 2 Years from Transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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umbilical cord blood transplant