Donor Natural Killer Cells and Aldesleukin in Treating Patients w/High Risk AML Undergoing Donor Stem Cell Transplant

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy, such as fludarabine phosphate and cyclophosphamide, and total body irradiation, before peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells and natural killer (NK) cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving IL-2 (aldesleukin) after NK cell infusion may stimulate them to kill any remaining cancer cells. PURPOSE: This phase I/II (currently enrolling in phase II) trial is studying how well a donor natural killer cell infusion works in treating patients who are undergoing donor stem cell transplant for acute myeloid leukemia.

Detailed Description
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OBJECTIVES: Primary To determine the disease-free survival at 6 months and 1 year in patients with high-risk myeloid malignancies who undergo a reduced-intensity haploidentical hematopoietic stem cell transplantation (HSCT) supplemented with donor natural killer (NK) cells. Secondary To evaluate the in vivo expansion of a donor CD3- CD19- selected NK cell product administered after a preparative regimen of cyclophosphamide, fludarabine, and total body irradiation (TBI) and HSCT in these patients. To determine the rate of graft failure defined by absolute neutrophil count (ANC) < 500/mm³ by day 28. To determine the incidence of grade III-IV acute graft-versus-host disease (GVHD) at 6 months. To determine the rate of treatment-related mortality at day 100. To determine the incidence of chronic GVHD at 12 months. To determine the incidence of disease relapse at 12 months. To determine the incidence of post-transplant lymphoproliferative disorder at 12 months. Correlative To correlate immune reconstitution of the in vivo expanded haploidentical NK cells with clinical outcomes. OUTLINE: This is an open-label study. Patients receive fludarabine intravenous (IV) over 1 hour on days -18 to -14 and cyclophosphamide IV over 2 hours on days -16 and -15. Patients receive cyclosporin A on Day -15 through Day -8. Patients undergo total body irradiation on day -13. Patients then receive an infusion of donor natural killer cells on day -12 and interleukin-2 subcutaneously on alternating days between days -12 to -2. Patients receive thymoglobulin (ATG) and undergo allogeneic peripheral blood stem cell transplantation on day 0. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 90 patients will be accrued for this study.

Official Title
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Reduced Intensity Haploidentical Hematopoietic Stem Cell Transplantation (HSCT) Supplemented With Donor Natural Killer (NK) Cell Infusions in Patients With High Risk Myeloid Malignancies Who Are Unsuitable for Fully Myeloablative Transplantation

Conditions
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Acute Myelogenous Leukemia

Intervention / Treatment
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* Biological: aldesleukin
* Biological: natural killer cells
* Drug: cyclophosphamide
* Drug: fludarabine phosphate
* Procedure: allogeneic hematopoietic stem cell transplantation
* Radiation: total body irradiation
* Biological: Thymoglobulin
* Drug: Cyclosporin A
* Drug: cyclophosphamide
* Drug: fludarabine phosphate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 4.2 High risk acute myeloid leukemia (AML) fitting within one of the following disease groups: Primary induction failure defined as no complete remission (CR) after two or more induction cycles. For primary induction failure (PIF) or refractory AML, the patient must have <5% circulating blasts (and <1000 absolute circulating blasts) beyond Day 28 after last chemo. During work-up period if circulating blasts rise above these levels, the patient is ineligible. The use of hydrea or other non-induction cytotoxic agents is not allowed to reduce blasts and achieve this eligibility. If the blasts are higher than these limits, the patient should be treated on an alternative therapeutic protocol or receive another reinduction attempt. (See section 7 regarding final check of blast status within 7 days of preparative regimen start). Relapsed AML with low disease burden must have less than 5% marrow blasts at time of enrollment for patients who did not receive re-induction or measured at least 28 days from the start of reinduction therapy for patients who did receive re-induction (maximum of 2 re-induction attempts). Patients who have relapsed more than 12 months following a prior HCT and did not reach CR following one re-induction cycle but have less than 10% marrow blasts are eligible. CR3 or greater. This will include CRp defined as CR without platelet recovery to 100,000/mcL. CR1 or CR2 with high risk features (therapy induced, prior myelodysplastic syndrome [MDS] or myeloproliferative disease [MPD], high risk cytogenetic or molecular phenotype) with no available alternate (sibling, unrelated donor [URD] or umbilical cord blood [UCB]) donors. Patients with prior central nervous system (CNS) involvement are eligible provided that it has been treated and CFS must be clear for at least 2 weeks prior to enrollment. Available related HLA-haploidentical donor (3-5 of 6 HLA, A, B and DRB1 matched) Karnofsky performance status > 50 Pulmonary Function: oxygen saturation ≥ on room air and diffusion lung capacity for carbon monoxide (DLCOcor) ≥ 40% Cardiac Function: Ejection fraction (EF) ≥ 30%, no uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to Day 0 Women of child bearing potential must have a negative pregnancy test within 14 days prior to study registration and agree to use adequate birth control during study treatment Human anti-mouse antibody (HAMA) monitoring: All subjects will be questioned about prior exposure to antibody therapy (including OKT3, rituximab, trastuzumab, etc). For subjects with no prior antibody therapy exposure, no further action will be taken For subjects who have received previous antibody therapies 10 ml of serum will be drawn before starting therapy. The presence of HAMA will not preclude proceeding with treatment. Voluntary written consent signed before performance of any study related procedure not part of the normal medical care. Exclusion Criteria: Biphenotypic leukemia New or progressive pulmonary infiltrates on screening chest x-ray or chest computed tomography (CT) scan that has not been evaluated with bronchoscopy, if feasible. Infiltrates attributed to infection must be stable/improving (with associated clinical improvement) after 1 week of appropriate therapy (2 weeks for presumed or documented fungal infections). Surgical resection waives any waiting requirements. Uncontrolled bacterial or viral infections. Chronic asymptomatic viral hepatitis is allowed. Known hypersensitivity to any of the study agents used Received other investigational drugs within the 14 days before enrollment Donor Selection: 12-75 years of age > 40 kilogram body weight In general good health as determined by the evaluating physician Donors must be HLA-A, B, DRB1 haploidentical (3-5/6 antigens HLA, A, B, DRB1) match to recipient. Patients and donors will be typed for HLA-A, B and C using at least intermediate resolution DNA techniques for DRB1 at high (allele) resolution. KIR B genotyping will be done on all haploidentical donors, and when feasible, the donor with the most favorable KIR gene profile will be used. Able and willing to have up to 4 separate apheresis collections per formed Not pregnant Human immunodeficiency virus (HIV): HIV-1, HIV-2 negative; HTLV-1, HTLV-2 negative, Hepatitis B and C negative Voluntary written consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SCT w/Donor Natural Killer Cells - short schema<br>Patients with high risk myeloid malignancies undergoing allogeneic hematopoietic stem cell transplantation, receiving fludarabine phosphate (daily dose of 40mg/m^2), cyclophosphamide (administered on Day -15 only), cyclosporin A, total body irradiation, natural killer cells, aldesleukin, and thymoglobulin. | Biological: aldesleukin<br>* Administered subcutaneously (SQ) 9 million units every other day beginning Day -12 through -2 (evening of natural killer cell infusion) for a total of 6 doses.<br>* Other names: IL-2;Biological: natural killer cells<br>* Infusion given on Day -12; The targeted infused cell dose of CD3- CD19- selected NK product is within the range of 2-3 x 10^7 cells/kg.<br>* Other names: therapeutic allogeneic lymphocytes;Drug: cyclophosphamide<br>* Administered intravenously (IV) 50 mg/kg on Day -15<br>* Other names: Cytoxan;Drug: fludarabine phosphate<br>* Administered intravenously (IV) 40 mg/m^2 on Days -18 through -14<br>* Other names: Fludara;Procedure: allogeneic hematopoietic stem cell transplantation<br>* On day 0, patients will receive an allogeneic transplant using pool cells from the day -1 and day 0 PBSC which will be CD34+ selected as the donor graft. The graft will be infused over 15-60 minutes.<br>* Other names: PBSC;Radiation: total body irradiation<br>* Administered on Day -13, 200 cGy two times.<br>Biological: Thymoglobulin<br>* intravenous (IV) 3 mg/kg on Day 0 (day of donor CD34 cell infusion)<br>* Other names: rabbit ATG;Drug: Cyclosporin A<br>* 1.5 mg/kg by mouth or intravenously for target dose range of 150-250; day -15 through day -8.<br>* Other names: CSA;|
| Experimental: SCT w/Donor Natural Killer Cells - extended schema<br>Patients with high risk myeloid malignancies undergoing allogeneic hematopoietic stem cell transplantation, receiving fludarabine phosphate (daily dose of 35mg/m^2), cyclophosphamide (administered on Days -15 and -16), cyclosporin A, total body irradiation, natural killer cells, aldesleukin, and thymoglobulin. | Biological: aldesleukin<br>* Administered subcutaneously (SQ) 9 million units every other day beginning Day -12 through -2 (evening of natural killer cell infusion) for a total of 6 doses.<br>* Other names: IL-2;Biological: natural killer cells<br>* Infusion given on Day -12; The targeted infused cell dose of CD3- CD19- selected NK product is within the range of 2-3 x 10^7 cells/kg.<br>* Other names: therapeutic allogeneic lymphocytes;Procedure: allogeneic hematopoietic stem cell transplantation<br>* On day 0, patients will receive an allogeneic transplant using pool cells from the day -1 and day 0 PBSC which will be CD34+ selected as the donor graft. The graft will be infused over 15-60 minutes.<br>* Other names: PBSC;Radiation: total body irradiation<br>* Administered on Day -13, 200 cGy two times.<br>Biological: Thymoglobulin<br>* intravenous (IV) 3 mg/kg on Day 0 (day of donor CD34 cell infusion)<br>* Other names: rabbit ATG;Drug: Cyclosporin A<br>* 1.5 mg/kg by mouth or intravenously for target dose range of 150-250; day -15 through day -8.<br>* Other names: CSA;Drug: cyclophosphamide<br>* Administered intravenously (IV) 50 mg/kg on Days -16 and -15<br>* Other names: Cytoxan;Drug: fludarabine phosphate<br>* Administered intravenously (IV) 35 mg/m^2 on Days -18 through -14<br>* Other names: Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival at 6 Months | Number of patients alive without evidence of disease at 6 months after transplant | Month 6 | 
| Disease-free Survival at 1 Year | Number of patients alive without evidence of disease at 1 year after transplant | 1 Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In Vivo Expansion of a Donor NK Cells NK Cell Product | Number of patients with in vivo expansion of donor NK cells. In vivo expansion of NK cell is defined as detection of >100 donor-derived NK cells per microliter of blood. | 12 - 14 days after NK cell infusion | 
| Number of Patients With Graft Failure | Number of patients with graft failure defined as <500 donor neutrophils count by day 28 in the absence of residual or relapsed leukemia | Day 28 | 
| Incidence of Grade III-IV Acute Graft Versus Host Disease | Grade III-IV acute graft versus host disease is a severe short term complication created by infusion of donor cells into a foreign host | Month 6 | 
| Number of Patients With Treatment-Related Mortality | Death within the first 100 days related to treatment in patients without relapse or persistent disease. | Day 100 | 
| Incidence of Chronic Graft Versus Host Disease | Chronic graft versus host disease is a severe long term complication created by infusion of donor cells into a foreign host | 1 Year | 
| Number of Patients With Disease Relapse | Disease relapse is the recurrence of leukemia in patients who had cleared their leukemia after treatment. Patients with persistent leukemia are not evaluable for relapse. | 1 Year | 
| Incidence of Post-transplant Lymphoproliferative Disorder (PTLD) | Post-transplant lymphoproliferative disorder (PTLD) is a virally-driven cancer of the lymphoid cells caused by immunosuppressive drugs taken after allogeneic stem cell transplantation to prevent or control graft versus host disease. | 1 Year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NK cells, natural killer cells, immunotherapy, hematopoietic cell transplant, acute myelogenous leukemia