Phase 1-2 MAHCT w/ TCell Depleted Graft w/ Simultaneous Infusion Conventional and Regulatory T Cell

Study Overview
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Brief Summary
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For patients with hematologic malignancies undergoing allogeneic myeloablative (MA) HCT with a T cell depleted graft, the infusion of naturally occurring regulatory T cells with conventional T cells (T cell add back) in pre-defined doses and ratios will reduce the incidence of acute graft vs host disease while augmenting the graft vs leukemia effect and improving immune reconstitution.

Detailed Description
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Primary Objectives: To determine the efficacy, safety and feasibility of administration of several dose combinations of conventional T cells (Tcon) and regulatory T cells (Treg) in patients undergoing allogeneic hematopoietic cell transplantation (HCT) with HLA matched donors (related or unrelated) using a T cell depleted graft [CD34+ hematopoietic progenitor cells (CD34+ HSPC)], without immune suppression. To determine the maximum tolerated dose of infused regulatory and conventional T cells in the matched donor setting To determine 1 year event free survival (EFS) post HCT Secondary Objectives: To determine the 1 year OS in patients undergoing allogeneic HCT with matched donors. To measure the incidence and severity of acute and chronic graft vs host disease (GvHD) To measure incidence of serious infections

Official Title
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Phase 1-2 Trial for Patients With Advanced Hematologic Malignancies Undergoing Myeloablative Allogeneic HCT With a T-cell Depleted Graft With Infusion of Conventional T-cells and Regulatory T-cells

Conditions
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Myeloid Leukemia, Chronic, Acute Myelogenous Leukemia, Myelodysplastic Syndromes (MDS), Lymphoma, Non-Hodgkin, Acute Lymphoblastic Leukemia (ALL), Myeloproliferative Syndrome, Acute Myeloid Leukemia, Acute Leukemia, Chronic Myelogenous Leukemia

Intervention / Treatment
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* Biological: Conventional T cells (Tcon) and Regulatory T cells (Treg)


Participation Criteria
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Eligibility Criteria
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Recipient Inclusion Criteria Patients with the following diseases that are histopathologically confirmed are eligible Acute leukemia, primary refractory or beyond CR1, or minimal residual disease (MRD) positivity. High risk acute myeloid leukemia in CR1 with any of the following features: Complex karyotype(≥3 clonal chromosomal abnormalities) Any of the following high risk chromosomal abnormalities: Monosomal karyotype (-5, 5q-, -7, 7q-) t(11q23), t(9;11), inv(3), t(3;3) t(6;9) t(9;22) Normal karyotype with fms-like tyrosine kinase 3 (FLT3)-ITD mutation Other high risk features as determined by molecular studies, or clinical presentation as assessed by the treating physician Chronic myelogenous leukemia (accelerated, blast or second chronic phase) Myelodysplastic syndromes Myeloproliferative syndromes Non-Hodgkin lymphoma with poor risk features not suitable for autologous HCT Age ≥18 yo and ≤ 60 yo for patients in Cohort 1 only. At the start of Cohort 2A and beyond, eligibility will be expanded to allow pediatric patients age ≥ 13 yo. Cardiac ejection fraction ≥ 45% Lung diffusion capacity ≥ 50% Calculated creatinine clearance ≥ 50 cc/min Serum glutamic-pyruvic transaminase( SGPT) and serum glutamic-oxaloacetic transaminase (SGOT) ≤ 3.0 x ULN (Upper limit of normal), unless elevated secondary to disease. Total bilirubin ≤ 2 x ULN (patients with Gilbert's syndrome may be included at the discretion of the PI or where hemolysis has been excluded Availability of a HLA matched donor (related or unrelated) defined by Class I (HLA-A and B) serologic typing (or higher resolution) and Class II (HLA DRB1) molecular typing. An HLA matched donor is defined for this study to be a sibling that is HLA matched 6/6; or an unrelated donor that is HLA matched 6/6 or 5/6. A sibling may be a half sibling. Karnofsky performance status ≥70% Recipient Exclusion Criteria Seropositive for any of the following: HIV ab; hepatitis B sAg; hepatitis C ab Prior myeloablative therapy or hematopoietic cell transplant Candidate for autologous transplant HIV positive Active uncontrolled bacterial, viral or fungal infection, defined as currently taking antimicrobial therapy and progression of clinical symptoms. Uncontrolled central nervous system (CNS) disease involvement Pregnant or a lactating female Positive serum or urine beta human chorionic gonadotropin (HCG) test in females of childbearing potential within 3 weeks of registration Psychosocial circumstances that preclude the patient being able to go through transplant or participate responsibly in follow up care Donor Inclusion Criteria Age ≥13 yo and ≤ 75 years Karnofsky performance status of ≥ 70% defined by institutional standards Seronegative for HIV 1 RNA (polymerase chair reaction (PCR); HIV 1 and HIV 2 ab (antibody); HTLV 1 and HTLV 2 ab; PCR+ or sAg (surface antigen) hepatitis B ; or PCR+ or sAg for hepatitis C; negative for the Treponema pallidum antibody Syphilis screen; and negative for HIV 1 and hepatitis C by nucleic acid testing (NAT) within 30 days of apheresis collection. In the case that T pallidum antibody tests are positive, donors must: Be evaluated and show no evidence of syphilis infection of any stage by physical exam and history Have completed effective antibiotic therapy to treat syphilis Have a documented negative non treponemal test (such as RPR) or in the case of a positive non treponemal test must be evaluated by an infectious disease expert to evaluate for alternative causes of test positivity and confirm no evidence of active syphilitic disease Must be 6/6 matched sibling donor as determined by HLA typing Female donors of child-bearing potential must have a negative serum or urine beta-HCG test within three weeks of mobilization Capable of undergoing leukapheresis, have adequate venous access, and be willing to undergo insertion of a central catheter should leukapheresis via peripheral vein be inadequate Agreeable to 2nd donation of Peripheral blood stem cell (PBPC) (or bone marrow harvest) in the event of graft failure The donor or legal guardian greater than 18 years of age, capable of signing an institutional review board (IRB-approved consent form. Donor Exclusion Criteria Evidence of active infection or viral hepatitis HIV positive Medical, physical, or psychological reason that would place the donor at increased risk for complications from growth factor or leukapheresis Lactating female

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Dose escalation<br>For the Phase I arm of the study the addition of planned numbers and ratios of Treg compared to Tcon will occur at defined time points after hematopoietic cell infusion. Each cohort will have 3 patients per group. The initial doses and ratios utilized will be 1 x 10^6/kg of T reg cells to 3x10^6/kg of Tcon cells at a 1:3 ratio. In order to progress to the next dose level, there must be no evidence of grade 3 or 4 acute GVHD. | Biological: Conventional T cells (Tcon) and Regulatory T cells (Treg)<br>* A baseline cell dose of conventional T cells of 1x10^6/kg will be used with escalation to the maximum tolerated dose up to 1x10^7/kg<br>* Other names: Purified regulatory T cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GvHD free Relapse free Survival (GRFS) | GvHD-free is defined as no GvHD symptoms, and relapse free survival is defined as survival at 12 months without relapse. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) | Dose-limiting Toxicity (DLT) was assessed as: Absolute neutrophil count <500/µL, to 28 day Cytokine release syndrome/acute infusion reactions as CTCAE Grade 3 to 5 Grade 3 to 4 acute GvHD. GvHD was staged as follows: 1: Skin: rash <25%. Liver: bilirubin (BIL) 2-3mg/dL. Gut: diarrhea (DIA) 500-1000 mL/day 2: Skin: rash 25-50%. Liver: BIL 3-6mg/dL. Gut: DIA 1001-1500 mL/day 3: Skin: rash > 50%. Liver: BIL 6-15mg/dL. Gut: DIA >1501-2000 mL/day 4: Skin: generalized erythroderma. Liver: BIL >15mg/dL. Gut: DIA >2001 mL/day GvHD was graded as follows. 1: Skin Stage 1-2; No Liver stage; No Gut stage 2: Skin Stage 1-3 ; Liver Stage 1; +/- Gut Stage 1 3: Skin Stage 2-3, Liver Stage 2-4; +/- Gut Stage 2-3 4: Skin Stage 2-4; Liver Stage 2-4; +/- Gut Stage 2-4 The outcome is reported as the number of participants who received both Treg and Tcon cell infusions and had DLT events, per treatment level, a number without dispersion. | 28 days | 
| Overall Survival (OS) | Overall Survival (OS) at 1 year was assessed as the number of participants per treatment level that received the hematopoietic cell transplant (HCT), and remained alive 12 months later, a number without dispersion. | 1 year | 
| Incidence and Severity of Chronic GvHD | Incidence and severity of chronic GvHD wil be assessed in participants who received the hematopoietic cell transplant (HCT). Stage of chronic GvHD was assessed as follows. Stage 1: Skin: rash <25% of skin. Liver: bilirubin 2-3mg/dL. Gut: diarrhea 500-1000 mL/day Stage 2: Skin: rash 25-50% of skin. Liver: bilirubin 3-6mg/dL. Gut: diarrhea 1001-1500 mL/day Stage 3: Skin: rash > 50% of skin. Liver: bilirubin 6-15mg/dL. Gut: diarrhea >1501-2000 mL/day Stage 4: Skin: generalized erythroderma. Liver: bilirubin >15mg/dL. Gut: diarrhea >2001 mL/day Grade of chronic GvHD was determined as follows. Grade 1: Skin Stage 1-2; No Liver stage; No Gut stage Grade 2: Skin Stage 1-3 ; Liver Stage 1; +/- Gut Stage 1 Grade 3: Skin Stage 2-3, Liver Stage 2-4; +/- Gut Stage 2 to 3 Grade 4: Skin Stage 2-4; Liver Stage 2-4; +/- Gut Stage 2 to 4 The outcome is reported as the number of participants by cGvHD grade and treatment level, a number without dispersion. | 2 years | 
| Incidence of Serious Infections | The outcome is reported as the number of serious infections per treatment level, in participants who received the hematopoietic cell transplant (HCT), a number without dispersion. | 24 months | 
| Concomitant Single-agent Immunosuppression | During Phase 2, stage 1, concomitant single-agent immunosuppression will be assessed as in participants receiving fresh Treg cells. The outcome is reported as number of such participants who received single-agent immunosuppression, by treatment level, a number without dispersion. | 2 years |