CD3/CD19 Depleted or CD3 Depleted/CD56 Selected Haploidentical Donor Natural Killer (NK) Cell Based Therapy for AML Patients Not in CR

Study Overview
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Brief Summary
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This is a phase II trial designed to test the safety and efficacy (complete response [CR]) of related donor HLA-haploidentical NK-cell based therapy for the treatment of acute myelogenous leukemia (AML). Patients with newly diagnosed AML who failed to achieve a complete remission (CR) after one or two standard induction attempts receive after a preparative regimen of cyclophosphamide and fludarabine a single infusion of CD3-/CD19- NK cells or CD3-/CD56+ NK cells followed by a short course of Interleukin-2 (IL-2) to facilitate NK cell survival and expansion.

Detailed Description
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This trial uses a Simon's two-stage design to estimate the complete remission rate at day +42 post NK cell infusion. The trial includes an initial randomized sub- study of 24 patients during stage 1 to choose which of the enriched NK cell products (CD3-/CD19- versus CD3-/CD56+) should be used to complete the trial based on successful in vivo NK cell expansion. This parameter is defined as 40% donor DNA and 40% of lymphocytes are NK cells at day 7 post infusion OR 20% donor DNA and 20% of lymphocytes are NK cells at day 14 post infusion. Twelve patients will be randomized to each product. Enrollment Plan: Stage 1: Enroll 24 patients with 1:1 randomization for NK cell processing (CD3-/CD19- versus CD3-/CD56+) Stage 2: Enroll an additional 17 patients using the optimal NK cell product identified during stage 1. If neither product achieves success at the end of stage 1, the study will stop and the platform redesigned

Official Title
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A Randomized Trial Comparing CD3/CD19 Depleted or CD3 Depleted/CD56 Selected Haploidentical Donor Natural Killer (NK) Cell Based Therapy for Adults With Acute Myelogenous Leukemia Who Have Failed 1 or 2 Induction Attempts

Conditions
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Acute Myelogenous Leukemia

Intervention / Treatment
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* Device: Interventions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed with acute myelogenous leukemia (except acute promyelocytic leukemia) and has failed one or two prior standard induction attempts. Failure is defined as: ≥ 30% bone marrow blasts with at least 20% cellularity at mid-cycle bone marrow biopsy or residual AML on subsequent  day 28 bone marrow biopsy by morphology, flow, PCR or FISH Patients enrolling after only 1 failed induction attempt must meet at least one of the following additional eligibility criteria of high risk: ≥ 60 years of age adverse cytogenetics or molecular characteristics AML that progressed out of myelodysplastic syndrome (MDS) is eligible if the patient did not receive treatment directed at the MDS HLA-haploidentical related donor (aged 12 to 70 years) ≥ 18, but < 75 years of age Karnofsky performance status ≥ 60% Adequate organ function within 14 days of study registration (30 days for pulmonary and cardiac) as defined in section 4.5 Ability to be off prednisone and other immunosuppressive drugs for at least 3 days prior to the NK cell infusion (excluding preparative regimen pre-meds) No prior hematopoietic transplant Not pregnant or lactating Sexually active females of childbearing potential and males with partners of child bearing potential must agree to use birth control Exclusion Criteria: Pregnant or lactating as the treatments used in this study includes drugs that are FDA Pregnancy Category D. Acute leukemias of ambiguous lineage AML that transformed from previously treated myelodysplastic syndromes Prior hematopoietic transplant New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that has not been cleared 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 HIV - chronic asymptomatic viral hepatitis is allowed Known hypersensitivity to one or more of the study agents used

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
Intervention Model: Single Group Assignment
Interventional Model Description: In summary, the study will take place in two parts: Stage 1: Enroll 24 patients with 1:1 randomization for NK cell processing (CD3-/CD19- versus CD3-/CD56+) Stage 2: Enroll an additional 17 patients using the optimal NK cell product identified during stage 1. If neither product achieves success at the end of stage 1, the study will stop and the platform redesigned
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single-arm trial<br>Multi-center, open-label, single-arm, phase I/II clinical trial | Device: Interventions<br>* CliniMACS® CD3 and CD19 Reagent System<br>* Other names: Devise;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Endpoint of the Study is Complete Remission (±3 Days) | Both the number of patients with leukemia in complete remission and the number of patients with leukemia not in complete remission will be reported. Leukemia remission status will be assessed according to the Revised Recommendations of The International Working Group (J Clin Oncol 21:4642-4649, 2003). | On Day+42 (+/- 3 days) after NK cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Secondary Endpoint is the Expansion and Persistence of NK Cells to be Used for the Remainder of the Study. | Successful expansion and persistence of NK cells is defined as ≥ 100 donor derived NK cells per µl blood. | Day+7 to Day+42 after NK cell infusion |