Clinical Trial Finder

Inclusion Criteria:

Recipient Inclusion Criteria. a. Patients with the following diseases that are histopathologically-confirmed are eligible.

• - Acute myeloid, lymphoid, or mixed phenotype leukemia in complete remission (CR) or CR with incomplete hematologic recovery (CRi) or beyond first complete remission (CR1) without the presence of minimal residual disease.

• - Acute myeloid, leukemia, or mixed phenotype leukemia that is either: - Not in morphologic CR with bone marrow infiltration by leukemic blasts of ≤10%, or.

• - In morphologic CR with evidence of minimal residual disease positivity by either multiparametric flow cytometric analysis or by a nucleic acid-based technique.

• - Primary refractory acute myeloid, lymphoid, or mixed phenotype leukemia.

• - Chronic myelogenous leukemia (accelerated, blast or second chronic phase) - Myelodysplastic syndromes.

• - Myeloproliferative syndromes b.

Match to the patient as follows: a. For Arm A1 (CLOSED):

• - Availability of a 8/8 or 7/8 HLA-matched donor (related or unrelated) defined by Class I (HLA-A, -B, -C) serologic typing (or higher resolution) and Class II (HLA-DRB1) molecular typing.

• - If the donor is a 7/8 HLA-match, the mismatch must be a permissive allelic mismatch as assessed by an independent HLA and transplantation expert.

b. For Arm A1 and Arm A3:

• - Availability of a 8/8 HLA-matched donor (related or unrelated) defined by Class I (HLA-A, -B, -C) serologic typing (or higher resolution) and Class II (HLA-DRB1) molecular typing.

c. For Arm B (CLOSED):

• - Availability of a haploidentical donor who is a ≥ 4/8 but <7/8 match at HLA-A, -B, -C, and -DRB1 (typed using DNA-based high-resolution methods), with at most one mismatch per locus d.

For Arm C1 (CLOSED) and C2:

• - Availability of a 8/8 HLA matched donor (related or unrelated) defined by Class I (HLA-A, B, C) serologic typing (or higher resolution) and Class II (HLA DRB1) molecular typing.

c. Age ≥ 18 and ≤75 years old at the time of enrollment. d. Left ventricular ejection fraction (LVEF) ≥ 45% e. Diffusing capacity of the lungs for carbon monoxide (DLCO) ≥ 50% f. Calculated creatinine clearance ≥ 50 mL/min or creatinine < 2.0 mg/dL g. SGPT and SGOT ≤ 3 x ULN, 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 h. Negative serum or urine beta-HCG test in females of childbearing potential within 3 weeks of registration i. Karnofsky performance status ≥ 70% Donor Inclusion Criteria. 1. Age ≥ 18 and ≤ 75 years of age. 2. Karnofsky performance status of ≥ 70% defined by institutional standards. 3. Seronegative for HIV-1 RNA 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 negative for hepatitis C; negative for the Treponema palladum antibody Syphillis screen; and negative for HIV-1 and hepatitis C by nucleic acid testing (NAT) within 30 days of apheresis collection. 4. In the case that T palladum antibody tests are positive, donors must: Be evaluated and show no evidence of syphilis infection of any stage by physical exam and history, or Have completed effective antibiotic therapy to treat syphilis, or 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 e. Match to the patient as follows: 1. Arm A1(CLOSED): • Must be a related or unrelated, 8/8 or 7/8-HLA match to recipient at HLAA, -B, -C, and -DRB1. If 7/8 HLA-matched, must be with permissive allelic HLA mismatch as assessed by an independent HLA and transplantation expert. 2. Arm A2 and Arm A3: • Must be a related or unrelated, 8/8 HLA match to recipient at HLA A, B, C, and DRB1. 3. Arm B (CLOSED):

• - Must be a haploidentical donor who is ≥ 4/8 but < 7/8 match at HLA-A, -B, -C, and -DRB1, with at most one mismatch per locus.

4. Arm C1 (CLOSED) and Arm C2:

• - Must be a related or unrelated 7/8 HLA matched to recipient at HLA A, B, C, DRB1 or -DQB1.

f. Must be willing to donate PBSC for up two consecutive days g. Female donors of child-bearing potential must have a negative serum or urine beta HCG test within 3 weeks of mobilization h. 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 i. Agreeable to 2nd donation of PBPC (or bone marrow harvest) in the event of graft failure j. The donor or legal guardian greater than 18 years of age, capable of signing an IRB approved consent form. k. Meets other criteria for donation as specified by standard NMDP guidelines (NMDP donors) or institutional standards (non-NMDP donors) l. Donors not meeting federal eligibility criterion, may nonetheless be included if either apply as follows per 21 CFR § 1271.65:

• - The donor is a first-degree or second-degree blood relative of the recipient, or.

• - Documented urgent medical need (DUMN), meaning no comparable human cell product is available and the recipient is likely to suffer death or serious morbidity without the human cell product, as attested by the Investigator or sub-investigator.

Exclusion Criteria:

Recipient Exclusion Criteria. 1. Seropositive for any of the following: HIV antibodies; hepatitis B surface antigen (sAg); hepatitis C antibodies. 2. Patients deemed candidates for fully myeloablative preparative conditioning regimens. d. Candidate for autologous transplant e. Hepatitis B or C with SGPT or SGOT > 3 x ULN f. HIV-positive g. Active uncontrolled bacterial, viral or fungal infection, defined as currently taking antimicrobial therapy and progression of clinical symptoms. h. Uncontrolled CNS disease involvement i. Pregnant or a lactating female j. Positive serum or urine beta-HCG test in females of childbearing potential within 3 weeks of registration k. Psychosocial circumstances that preclude the patient being able to go through transplant or participate responsibly in follow-up care l. Known allergy or hypersensitivity to, or intolerance of, tacrolimus m. Positive anti-donor HLA antibodies against a mismatched allele in the selected donor determined by either:

• - A positive crossmatch of any titer; or.

• - The presence of anti-donor HLA antibody to any HLA locus n.

Any uncontrolled autoimmune disease requiring active immunosuppressive treatment o. Concurrent malignancies or active disease within 1 year, except nonmelanomatous skin cancers that have been curatively resected. Donor Exclusion Criteria. 1. Evidence of active infection. 2. Seropositive for HIV-1 or-2, HTLV-1 or -2. 3. Medical, physical, or psychological reason that would place the donor at increased risk for complications from growth factor or leukapheresis. 4. Lactating female

The objectives for the study are listed below: Primary Objectives. *Determine the safety, and feasibility of administration of several dose combinations of conventional T-cells (Tcon) and regulatory T-cells (Treg) in subjects undergoing allogeneic hematopoietic cell transplantation (HCT) with related/unrelated HLA-matched or mismatched donors, or haploidentical donors with reduced intensity conditioning preparative regimen. Secondary Objectives.

• - To determine the GVHD-free relapse-free survival (GRFS) post-HCT.

• - To determine the overall survival (OS) post-HCT.

• - To measure the incidence and severity of acute and chronic GVHD.

Exploratory Objectives.

• - To measure the incidence of serious infections.

• - To measure the incidence and timing of engraftment.

- To measure T cell immunity reconstitution parameters

Arms

Experimental: Arm A1: Matched related/matched unrelated donor transplantation (closed)

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:. Fludarabine (160 mg/m2) Melphalan (50 mg/m2) TBI (4Gy) All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

Experimental: Arm B: Haploidentical transplantation (closed)

Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning: -. Fludarabine (160 mg/m2) Melphalan (100 mg/m2 TBI (4Gy) Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.

Experimental: Arm A2: Fully matched (8/8) related/unrelated donor transplantation

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant: Fludarabine (160 mg/m2) Thiotepa (10 mg/kg) TBI (4Gy) All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

Experimental: Arm A3: Fully (8/8) matched related/unrelated donor transplantation

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant: Fludarabine (160 mg/m2) Thiotepa (5 mg/kg) TBI (2-3 Gy). All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

Experimental: Arm C1:7/8 mismatched related/unrelated donor transplantation (closed)

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant: Fludarabine (160 mg/m2) Thiotepa (10 mg/kg) TBI (4 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).

Experimental: Arm C2: 7/8 mismatched related/unrelated donor transplantation

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant: Fludarabine (160 mg/m2) Thiotepa (5 mg/kg) TBI (2-3 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.

Interventions

Drug: - Purified regulatory T-cells (Treg) plus CD34+ HSPC

Purified regulatory T-cells (Treg) plus CD34+ hematopoietic progenitor cells ("CD34+ HSPC"), followed by conventional T-cells (Tcon) Manufactured at SCTT Laboratory, dose 1x10^6 cells/ kg to 3x10^6 cells/kg

Drug: - Fludarabine

Fludarabine (160 mg/m2)

Drug: - Melphalan

Melphalan (50 mg/m2)

Device: - CliniMACS CD34 Reagent System

The CliniMACS® CD34 Reagent System is a medical device that is used in vitro to select and enrich specific cell populations is manufactured by Miltenyi Biotec

Drug: - Tacrolimus

4-6ng/mL

Drug: - Cyclophosphamide

40mg/kg

Drug: - Plerixafor

Dose 0.24 mg/kg, manufactured by Genzyme

Drug: - Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent

Single-use vials contain either 300 mcg or 480 mcg filgrastim at a fill volume of 1.0 mL or 1.6 mL

Drug: - Thiotepa

Thiotepa 10 mg/kg

Drug: - Mycophenolate Mofetil (MMF)

MMF 1000 mg BID

Drug: - Ruxolitinib

Ruxolitinib 5 mg BID