NK Cell Based Non-Myeloablative Transplantation in Acute Myeloid Diseases

Study Overview
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Brief Summary
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This is a phase II multi-institutional therapeutic study of NK-cell based nonmyeloablative haploidentical transplantation for the treatment of high-risk acute myeloid diseases. Enrollment will use a two-stage design. Stage 1 will enroll 15 patients unless an early stopping rule is met. If 9 or more of these first 15 patients achieve leukemia free neutrophil engraftment at day +28 accrual will move to stage 2. In stage 2, an additional 28 patients will be enrolled for a total of 43 patients. Patients will be followed for disease response for 2 years.

Detailed Description
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A reduced intensity conditioning using Fludara, Cytoxan, and irradiation will start on day -22, followed by infusion of donor NK (natural killer) cells on day-17, 6 doses of interleukin-2 (IL-2) to promote NK expansion (day -17 to day -7), 2 doses of ATG for additional immunosuppression to promote engraftment (day -5 to -4), and infusion of a TCR α/β-depleted same donor graft on day 0.

Official Title
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Multi-Center Phase II Trial of NK Cell Based Non-Myeloablative Haploidentical Transplantation for Patients With High-Risk Acute Myeloid Diseases

Conditions
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Myelodysplastic Syndrome, Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Preparative Regimen
* Biological: NK Cells
* Drug: Interleukin-2
* Biological: CD34 Graft/Anti-thymocyte globulin
* Biological: Donor TCR α/β-depleted Graft/ATG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) RAEB-1 or RAEB-2 fitting within one of the following disease groups: Primary induction failure (PIF): Patients who have not achieved a complete remission (CR) after two induction cycles of cytotoxic therapy (i.e. 7+ 3, MEC, FLAG, etc.) and having ≤ 10,000 absolute circulating blasts measured at least 21 days from prior therapy. Hydroxyurea may be used to control blasts count. Demethylating agents do not count as induction therapy; however early re-induction therapy based on residual disease on a day 14 BM will count as a 2nd cycle Relapsed Disease with low disease burden (AML or MDS with ≤ 10,000 absolute circulating blasts. No re-induction attempts are required, but a maximum of 2 reinduction attempts are allowed to be 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: Includes therapy induced, prior MDS or MPD, high risk cytogenetic or molecular phenotype with no available donor (sibling or unrelated adult) Patients with known prior central nervous system (CNS) involvement are eligible provided that it has been treated and CSF is clear for at least 2 weeks prior to enrollment. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment. Available related HLA-haploidentical adult donor by at least Class I serologic typing at the A&B locus Karnofsky score > 50% Adequate organ function within 28 days of study registration defined as: Hepatic: AST ≤ 3 x upper limit of institutional normal, total bilirubin ≤ 2.0 mg/dl Renal: estimated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73m^2 Pulmonary: Oxygen saturation ≥ 90% on room air and DLCOcor ≥ 40% Cardiac: Ejection Fraction ≥ 35% and no uncontrolled angina, severe uncontrolled ventricular or arterial arrhythmias, or any evidence of acute ischemia or active conduction system abnormalities (rate controlled atrial fibrillation is not an exclusion) Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to NK cell infusion (except for those prescribed as part of the study) Women of child bearing potential must have a negative pregnancy test within 28 days prior to study registration and agree to use adequate birth control during study treatment Voluntary written consent Exclusion Criteria: Biphenotypic leukemia Allogeneic transplant for AML within previous 6 months New or progressive pulmonary infiltrates on screening chest x-ray or chest 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 (4 weeks for presumed or documented fungal infections). Uncontrolled bacterial, fungal or viral infections including HIV - chronic asymptomatic viral hepatitis is allowed Known hypersensitivity to any of the study agents Received any investigational drugs within the 14 days before 1st dose of fludarabine Requires agents other than hydroxyurea to control blast count Donor Selection: Related donor (sibling, parent, offspring, parent or offspring of an HLA identical sibling) 12-75 years of age. (It is recognized individual institutions may have differing donor age guidelines. This is acceptable as long as no donor is younger than 12 years or older than 75 years). Body weight of at least 40 kilograms In general good health as determined by the medical provider HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus Able and willing to have up to 4 separate apheresis collections Not pregnant Voluntary written consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: CD34 Schema - High-Risk Acute Myeloid Disease<br>Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor. | Drug: Preparative Regimen<br>* Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant,<br>* Other names: radiation;Biological: NK Cells<br>* CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.<br>* Other names: Natural Killer cells;Drug: Interleukin-2<br>* Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion<br>* Other names: IL-2;Biological: CD34 Graft/Anti-thymocyte globulin<br>* Single donor filgrastim mobilized CD34+ selected peripheral blood stem cell graft (minimum cell dose of 5 x 10^6/kg) on day 0. Rabbit anti-thymocyte globulin (ATG) will be administered on day -1 (0.5 mg/kg) and day +1 and +2 (2.5 mg/kg) pretransplant per institutional guidelines. ATG dosing not identical for all patients.<br>* Other names: ATG;|
| Experimental: TCRα/β Schema - High-Risk Acute Myeloid Disease<br>Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and same donor TCR α/β-depleted cells infusion. | Drug: Preparative Regimen<br>* Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant,<br>* Other names: radiation;Biological: NK Cells<br>* CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.<br>* Other names: Natural Killer cells;Drug: Interleukin-2<br>* Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion<br>* Other names: IL-2;Biological: Donor TCR α/β-depleted Graft/ATG<br>* Single donor TCR α/β-depleted filgrastim-mobilized peripheral blood stem cells (PBSC) graft (minimum cell dose of 5 x 10^6/kg) on day 0. ATG will be administered on days -6 and -5 (3mg/kg) for most patients.<br>* Other names: stem cell graft;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Donor Neutrophil Engraftment | The rate of donor neutrophil engraftment in the absence of leukemia at day +28 will be determined. Successful neutrophil engraftment is defined as an absolute donor-derived neutrophil count of >500 cells/μl. Leukemia free is defined as <5% bone marrow blasts, absence of blasts with Auer rods; absence of extramedullary disease; but cytogenetic or molecular minimal residual disease is allowed. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Disease Free Survival |  | At 6 Months | 
| Number of Participants With Treatment Related Mortality (TRM) | Cumulative incidence will be used to estimate TRM. | At 6 Months | 
| Number of Participants Who Relapse | Cumulative incidence will be used to estimate relapse. | 2 Years | 
| Number of Participants With Early In Vivo Expansion of Natural Killer (NK) Cells | Successful in vivo donor NK cell expansion will be defined by measuring an absolute circulating donor-derived NK cell count of >100 cells/μl in patient's peripheral blood 12 days after infusion. | Day 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-myeloablative haploidentical transplant, hematopoietic cell transplant, natural killer cells, adoptive cellular therapy