QUILT-3.033: Haplo NK With SQ ALT-803 for Adults With Relapsed or Refractory AML

Study Overview
=================
Brief Summary
-----------------
This is a multi-institutional Simon's optimal two-stage phase II trial of CD3/CD19 depleted, ALT-803 activated, haploidentical donor NK cells and subcutaneous ALT-803 given after lymphodepleting chemotherapy (CY/FLU) for the treatment of refractory or released acute myelogenous leukemia (AML).

Official Title
-----------------
QUILT-3.033: Haploidentical Donor Natural Killer (NK) Cell Infusion With Subcutaneous ALT-803 in Adults With Refractory or Relapsed Acute Myelogenous Leukemia

Conditions
-----------------
Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Biological: ALT-803


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of acute myeloid leukemia (AML) and meets one of the following disease criteria: Primary induction failure: De novo AML - no CR after 2 or more chemotherapy induction attempts Secondary AML (from MDS or treatment related): no CR after 1 or more chemotherapy induction attempts Relapse after chemotherapy: not in CR after 1, 2, or 3 re-induction attempts Patients > 60 years of age, the 1 cycle of chemotherapy is not required Relapse after hematopoietic stem cell transplant: Relapse must have occurred > 18 months after transplant No re-induction required and no more than 1 re-induction attempt is allowed Notes: For hypomethylating agents (i.e. decitabine, azacitidine) to count as an induction/re-induction attempt, the patient must have completed a minimum of 3 monthly cycles For targeting agents (i.e. sorafenib) to count as an induction/re-induction attempt, the patient must have completed a minimum of 1 month without attaining CR 7+3 followed by 5+2 counts as TWO induction attempts Use of hydroxyurea is permitted to control blasts until Day -3 per Section 8.7 A history of AML related CNS involvement is allowed if CSF analysis is negative on 2 test dates at least 2 weeks apart prior to study treatment. The use of ongoing CNS maintenance therapy is allowed while on study. HLA-haploidentical related donor (aged 12 to 75 years) with donor/recipient match based on a minimum of intermediate resolution DNA based Class I typing of the A and B locus (at least 2/4 class I allele) Karnofsky Performance Status ≥ 60% Adequate organ function within 14 days of study registration (28 days for pulmonary and cardiac) defined as: Creatinine: ≤ 2.0 mg/dL Hepatic: AST and ALT < 3 x upper limit of institutional normal Pulmonary Function: oxygen saturation ≥ 90% on room air; PFT's required only if symptomatic or prior known impairment - must have pulmonary function >50% corrected DLCO and FEV1. Cardiac Function: LVEF ≥ 40% by echocardiography, MUGA or cardiac MRI, 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 systemic immunosuppressive medications for at least 3 days prior to NK cell infusion (excluding preparative regimen pre-medications) . Sexually active females of child bearing potential and males with partners of child bearing potential must agree to use effective contraception during therapy and for 4 months after completion of therapy . Voluntary written consent prior to the performance of any research related procedures. Exclusion Criteria: Acute leukemias of ambiguous lineage Pregnant or breastfeeding - The agents used in this study include those that fall under Pregnancy Category D - have known teratogenic potential. Women of child bearing potential must have a negative pregnancy test at screening Active autoimmune disease requiring systemic immunosuppressive therapy History of severe asthma and currently on systemic chronic medications (mild asthma requiring inhaled steroids only is eligible) New or progressive pulmonary infiltrates on screening chest X-ray or chest CT scan unless cleared for study 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-1/2 or active hepatitis C/B - chronic asymptomatic viral hepatitis is allowed Received any investigational agent within the 14 days before the start of study treatment (1st dose of fludarabine) Prior ALT-803

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cy, FLU, Haplo NK and ALT-803<br>Preparative Regimen of Fludarabine and Cyclophosphamide ALT-803 Activation of Donor NK Cells ALT-803 to Facilitate NK Cell Survival and Expansion | Biological: ALT-803<br>* Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 ALT-803 Stimulated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be stimulated by overnight incubation with 36.1 ng/mL ALT-803 under GMP conditions and infused on day 0. ALT-803 to Facilitate NK Cell Survival and Expansion: ALT-803 at 10 mcg/kg subcutaneously (SC) with the 1st dose administered on day 0 (no sooner than 4 hours post NK cells), day +5 and day +10 for 3 doses total<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Remission With or Without Incomplete Platelet Recovery | To estimate the rate of complete remission with incomplete platelet recovery (CRp) - defined as leukemic clearance and neutrophil recovery without platelet recovery - by day 42 after the infusion of CD3/CD19 depleted, ALT-803 stimulated, donor NK cells and subcutaneous ALT-803 given after a non-myeloablative preparative regimen for the treatment of refractory or released acute myelogenous leukemia (AML) | Day 42 post NK cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of in Vivo Expansion ≥100 of Donor Derived NK Cells Per /μl Blood | Number of patients with successful in vivo NK-cell expansion which is defined by measuring an absolute circulating donor-derived NK cell count of ≥100 cells/μl in patient's peripheral blood. | Day 14 post NK cell infusion | 
| Number of Participants Experiencing ALT-803 Associated Toxicity | Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) | Day 0 | 
| Number of Participants Experiencing ALT-803 Associated Toxicity | Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) | Day 5 | 
| Number of Participants Experiencing ALT-803 Associated Toxicity | Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) | Day 7 | 
| Number of Participants Experiencing ALT-803 Associated Toxicity | Toxicity will be classified and graded according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) | Day 10 | 
| Number of Participants With Treatment Related Mortality | To evaluate the safety of the therapy as measured by rate of treatment related mortality (TRM) at 6 months | 6 months post-therapy |