CD8 Depleted, Non-engrafting, HLA Mismatched Unrelated Infusion With MDS and Secondary AML

Study Overview
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Brief Summary
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The purpose of the study is to determine the safety of an investigational treatment for myelodysplastic syndrome (MDS) after the first therapy (such as azacitidine or decitabine) stops working or after progression of MDS to acute myeloid leukemia (AML). Funding source - FDA OOPD.

Detailed Description
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The purpose of the study is to determine the safety of an investigational treatment for myelodysplastic syndrome (MDS) after the first therapy (such as azacitidine or decitabine) stops working or after progression of MDS to acute myeloid leukemia (AML). Patients with advanced MDS are treated with hypomethylating agents (HMAs) such as azacitidine or decitabine. These medications can be effective for a few months to a few years, but usually lose effect eventually. This study is attempting to design a therapy called non-engrafting, CD8 depleted donor lymphocyte infusion or NE-DLI as a treatment for these diseases.

Official Title
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CD8 Depleted, Non-Engrafting, HLA Mismatched Unrelated Donor Lymphocyte Infusion in Patients With MDA and Secondary AML

Conditions
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Myelodysplastic Syndromes, Secondary Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: CD8 Depleted, Non-engrafting,HLA mismatched unrelated donor lymphocytes
* Drug: Standard of Care Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Myelodysplastic Syndrome (MDS) having failed hypomethylating agent (HMA) therapy cohort: Age 18-79 years, inclusive Pathologically confirmed MDS or myelodysplastic/myeloproliferative overlap (MDS/MPN) IPSS-R score intermediate, high or very high Must have failed therapy with an HMA (defined as lack of response by International Working Group criteria (1) or intolerance of the drug) Secondary Acute Myeloid Leukemia (sAML): Pathologically confirmed AML according to World Health Organization (WHO) criteria Evidence of an antecedent hematologic disorder (AHD) prior to acute leukemia including a known prior diagnosis of MDS, MPN or MDS/MPN or data suggestive of an AHD such as cytopenias, fibrosis, macrocytic anemia, cellular or dysplasia at or prior to the time of diagnosis. If available, MDS-defining karyotypes (-7/del(7q), -5/del(5q), del(13q), del(11q), del(12p), t(12p), del(9q), idic(X)(q13), t(17p) (unbalanced translocations) or i(17q) (ie, loss of 17p), t(11;16)(q23;p13.3), t(3;21)(q26.2;q22.1), t(1;3)(p36.3;q21), t(2;11)(p21;q23), inv(3)(q21q26.2), t(6;9)(p23;q34)) or somatic mutations in multiple genes including p53, TET2, JAK2, CALR, MPL, ASXL1, RUNX1, SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 would also confirm eligibility. Age 60-79 years, inclusive May be previously untreated For both cohorts: Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Deemed eligible to receive cytotoxic chemotherapy Creatinine clearance (CrCl)>50ml/min Total bilirubin <2 mg/dL (except for patients with Gilbert's disease), AST and ALT < 3x ULN Left Ventricular Ejection Fraction ≥ 50% Willing and able to participate in study assessments Exclusion Criteria: Patients who have had systemic chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Hydroxyurea during this period may be given as a bridging therapy to maintain disease stability while awaiting treatment. Intrathecal chemotherapy within this time frame is permitted. Intrathecal chemotherapy may be continued during protocol therapy in order to consolidate or maintain a central nervous system (CNS) remission, but not to treat active CNS disease Acute promyelocytic leukemia, or the presence of t(15;17) Patients receiving any other investigational agents Uncontrolled concurrent illness including, but not limited to, ongoing and uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in the fetus. Breastfeeding should be discontinued if the mother is treated. These potential risks may also apply to other agents used in this study Patients who have any debilitating medical or psychiatric illness that would preclude their giving informed consent or their receiving optimal treatment and follow-up Patients with a poor functional status of ECOG 3-4, or otherwise deemed unfit to tolerate induction chemotherapy. Patients with blastic transformation of chronic myelogenous leukemia are ineligible Exposure to a humanized mouse chimeric antibody, as this could sensitize patients to components of the CD8 depletion column that may be present in small amounts in the cell product Prior allogenic hematopoietic cell transplant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Level 1<br>All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at dose level 1: 1X10^6 CD4 T Cells/kg | Biological: CD8 Depleted, Non-engrafting,HLA mismatched unrelated donor lymphocytes<br>* Infusion of mononuclear cells, apheresis products depleted of CD8+ T cells using the CliniMACS® system with CliniMACS® CD8 reagent<br>Drug: Standard of Care Chemotherapy<br>* Standard of care cytarabine-based chemotherapy<br>|
| Experimental: Phase 1 Dose Level 2<br>All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at dose level 2: 1X10^7 CD4 T Cells/kg | Biological: CD8 Depleted, Non-engrafting,HLA mismatched unrelated donor lymphocytes<br>* Infusion of mononuclear cells, apheresis products depleted of CD8+ T cells using the CliniMACS® system with CliniMACS® CD8 reagent<br>Drug: Standard of Care Chemotherapy<br>* Standard of care cytarabine-based chemotherapy<br>|
| Experimental: Phase 1 Dose Level 3<br>All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at dose level 3: 5 X10^7 CD4 T Cells/kg | Biological: CD8 Depleted, Non-engrafting,HLA mismatched unrelated donor lymphocytes<br>* Infusion of mononuclear cells, apheresis products depleted of CD8+ T cells using the CliniMACS® system with CliniMACS® CD8 reagent<br>Drug: Standard of Care Chemotherapy<br>* Standard of care cytarabine-based chemotherapy<br>|
| Experimental: Phase 2 -Treatment at Maximum Tolerated Dose (MTD)<br>All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at MTD. | Biological: CD8 Depleted, Non-engrafting,HLA mismatched unrelated donor lymphocytes<br>* Infusion of mononuclear cells, apheresis products depleted of CD8+ T cells using the CliniMACS® system with CliniMACS® CD8 reagent<br>Drug: Standard of Care Chemotherapy<br>* Standard of care cytarabine-based chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of CD8 depleted non-engrafting HLA-mismatched unrelated donor lymphocytes infusion (NE-DLI) | Maximum Tolerated Dose will be determined by testing increasing doses of CD8 depleted non-engrafting HLA-mismatched unrelated donor lymphocytes infusion (NE-DLI). | Up to 60 days per dose level | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall Response Rate is defined as Complete Response + Partial Response using RECIST v1.1 criteria. | Up to 12 months | 
| Progression Free Survival | Progression Free Survival is defined as the time from enrollment to date of progression or death, or censor at last follow-up date. | Up to 12 months | 
| Overall Survival | Overall Survival is defined as the time from study enrollment to death from any cause or censored at last follow up date | Up to 12 months | 
| Hematologic Response | Hematologic response will be determined using International Working Group 2006 criteria for MDS patients and the International Working Group 2003 criteria for AML | Up to 12 months | 

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