QUILT-3.034: Non-Myeloablative TCRa/b Deplete Haplo HSCT With Post ALT-803 for AML

Study Overview
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Brief Summary
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This is a phase II multi-institutional therapeutic study of a non-myeloablative T cell receptor (TCR) alpha/beta depleted haploidentical transplantation with post-transplant immune reconstitution using ALT-803 for the treatment of high-risk myeloid leukemia (AML), treatment-related/secondary AML, and myelodysplastic syndrome (MDS).

Official Title
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QUILT-3.034: Multi-Center Trial of Non-Myeloablative TCRa/b Deplete Haploidentical Hematopoietic Cell Transplantation With Post HCT ALT-803 in High-Risk Myeloid Diseases

Conditions
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High-Risk Acute Myeloid Leukemia, Treatment-Related Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: ALT-803


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 to ≤70 years Meets one of the following disease and risk categories: High-Risk Acute Myeloid Leukemia (AML) with predicted risk of relapse higher than 30%, which includes, but not limited to the following: Patients in morphological remission (CR1 or beyond) with minimal residual disease as quantified either by flow cytometry, or by cytogenetics or molecular markers. Patients with the following karyotypes in morphological CR or CRi: ELN-Intermediate I, Adverse, ELN-Intermediate-II. (18) (Examples include monosomal karyotype, complex karyotype, mutant p53, mutant RUNX1, mutant ASXL1, mutant FLT3-ITD, mutant DNMT3A, Inversion 3, T(6:9), KIT mutated core binding factor AML) Treatment-Related AML and Secondary AML in morphological remission (CR1 or beyond) with minimal residual disease as quantified either by flow cytometry, or by cytogenetics or molecular markers Myelodysplastic Syndrome (MDS) with < 5% blasts by morphology and meets at least one of the following: Received intensive induction chemotherapy (i.e. 7+3 or MEC) OR Progression after 4 cycles of hypomethylating agents The donor and recipient must be HLA identical for at least one haplotype (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1 Karnofsky performance status ≥ 60% (appendix IV) Adequate organ function within 14 days of study registration (30 days for pulmonary and cardiac) defined as: Hepatic: AST and ALT < 3 x upper limit of institutional normal Renal: estimated glomerular filtration rate (GFR) ≥ 40 mL/min/1.73m2 Pulmonary: oxygen saturation ≥ 90% on room air with no symptomatic pulmonary disease. If symptomatic or prior known impairment DLCOcor ≥ 40%. Cardiac: 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 immunosuppressive medications for at least 3 days prior to transplant (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 Allogeneic transplant for AML within the previous 6 months (no time limit for autologous transplant) Active CNS disease - if a history of AML related CNS involvement, screening CSF analysis must be negative 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 Active concomitant second malignancy (i.e. has required treatment in the previous 6 months) Known hypersensitivity to any of the study agents Received any investigational drugs within the 14 days before 1st dose of fludarabine

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALT-803<br> | Biological: ALT-803<br>* A reduced intensity conditioning starts on Day -6, (CY/FLU/TBI/TLI) followed by infusion of a TCRα/β-deplete haploidentical graft on Day 0. Two doses of ALT-803 are given initially (early) 1 week apart to facilitate NK cell expansion. ALT-803 maintenance (late) for immune reconstitution begins at Day 42 and consists of 4 weekly doses, followed by 4 weeks off. Up to four 8 week treatment courses are permitted. No post-transplant GVHD prophylaxis is administered unless the final donor cell product contains > 2 x 105 α/β T cells/kg recipient weight.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of disease response | Rate of donor neutrophil engraftment in the absence of disease at Day +28. Neutrophil engraftment is defined as absolute neutrophil count (ANC) ≥ 5 X 10 8 /L. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DFS) | Incidence of disease free survival (DFS). | 12 months | 
| Treatment Related Mortality (TRM) | Incidence of treatment related mortality (TRM). | 12 months | 
| Disease Relapse | Incidence of disease relapse. | 12 months | 
| Grade II-IV acute Graft versus Host Disease (aGVHD) | Incidence of acute Graft versus Host Disease measured by the number of T-cells infused or NK cells engrafted causing GVHD syndrome. | Day 100 | 
| Serious Adverse Events from ALT-803 (Early Schedule) | Incidence of serious adverse events from ALT-803 will be measured for an initial 2 doses, given one week apart. | 1 Year | 
| Serious Adverse Events from ALT-803 (Late Schedule) | Incidence of serious adverse events from ALT-803 will be measured for 16 doses, given over 4 weeks. | 1 Year | 
| Chronic Graft versus Host Disease (cGVHD) | Incidence of chronic Graft versus Host Disease will be measured by the number of T-cells infused or NK cells engrafted causing GVHD syndrome. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, MDS