Reduced Intensity Allogeneic HCT in Advanced Hematologic Malignancies w/T-Cell Depleted Graft

Study Overview
=================
Brief Summary
-----------------
Reduced intensity conditioning (RIC) has been increasingly adopted as a modality to allow preparative conditioning pre-transplant to be tolerated by older adults or those patients that are otherwise unfit for myeloablative conditioning. In this study Reduced intensity conditioning (RIC) conditioning is used and followed by match aploidentical donor peripheral blood stem cell transplantation.

Detailed Description
-----------------
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) 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

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

Conditions
-----------------
Allogeneic Hematopoietic Cell Transplantation (HCT), Advanced Hematologic Malignancies, Acute Leukemia, Chronic Myelogenous Leukemia, Myelodysplastic Syndromes, Myeloproliferative Disorders

Intervention / Treatment
-----------------
* Drug: Purified regulatory T-cells (Treg) plus CD34+ HSPC
* Drug: Fludarabine
* Drug: Melphalan
* Device: CliniMACS CD34 Reagent System
* Drug: Tacrolimus
* Drug: Cyclophosphamide
* Drug: Plerixafor
* Drug: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Recipient Inclusion Criteria 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 Myelofibrosis that is transplant-eligible Myeloproliferative syndromes Blastic plasmacytoid dendritic cell neoplasm Non-Hodgkin lymphoma with poor risk features not suitable for autologous HCT Match to the patient as follows: a. For Arm A: 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 B: 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 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 ≤ 5 x ULN, unless elevated secondary to disease Total bilirubin ≤ 3 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 Age ≥ 18 and ≤ 75 years of age Karnofsky performance status of ≥ 70% defined by institutional standards 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. 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 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 e. Match to the patient as follows: a. Arm A: 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. b. Arm B: 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. 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) Exclusion Criteria: Recipient Exclusion Criteria Seropositive for any of the following: HIV antibodies; hepatitis B surface antigen (sAg); hepatitis C antibodies Prior myeloablative therapy or hematopoietic cell transplant Patients deemed candidates for fully myeloablative preparative conditioning regimens 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 CNS disease involvement Pregnant or a lactating female Positive serum or urine beta-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 Known allergy or hypersensitivity to, or intolerance of, tacrolimus Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥ 5 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 Any uncontrolled autoimmune disease requiring active immunosuppressive treatment Concurrent malignancies or active disease within 1 year, except nonmelanomatous skin cancers that have been curatively resected Donor Exclusion Criteria Evidence of active infection Seropositive for HIV-1 or-2, HTLV-1 or -2 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
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Matched related/matched unrelated donor transplantation<br>Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/unrelated donor transplant. All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus. Fludarabine (160 mg/m2)/ Melphalan (50 mg/m2)/TBI (4Gy) | Drug: Purified regulatory T-cells (Treg) plus CD34+ HSPC<br>* Purified regulatory T-cells (Treg) plus CD34+ hematopoietic progenitor cells (CD34+ HSPC), Manufactured at SCTT Laboratory, dose 1x10^6 cells/kg to 3x10^6 cells/kg<br>Drug: Fludarabine<br>* Fludarabine (160 mg/m2)<br>* Other names: fludarabine monophosphate;Drug: Melphalan<br>* Melphalan (50 mg/m2) in Arm A; Melphalan (100 mg/m2) in Arm B<br>* Other names: Melphalanum;Device: CliniMACS CD34 Reagent System<br>* 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<br>Drug: Tacrolimus<br>* 4-6ng/mL<br>* Other names: fujimycin;Drug: Cyclophosphamide<br>* 40mg/kg<br>* Other names: alkylating agent;Drug: Plerixafor<br>* Dose 0.24 mg/kg, manufactured by Genzyme<br>* Other names: LM-3100;Drug: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent<br>* Single-use vials contain either 300 mcg or 480 mcg filgrastim at a fill volume of 1.0 mL or 1.6 mL<br>* Other names: filgrastim XM02;|
| Experimental: Arm B: Haploidentical transplantation<br>Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning. Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus. Fludarabine (160 mg/m2)/ Melphalan (100 mg/m2)/TBI (4Gy) | Drug: Purified regulatory T-cells (Treg) plus CD34+ HSPC<br>* Purified regulatory T-cells (Treg) plus CD34+ hematopoietic progenitor cells (CD34+ HSPC), Manufactured at SCTT Laboratory, dose 1x10^6 cells/kg to 3x10^6 cells/kg<br>Drug: Fludarabine<br>* Fludarabine (160 mg/m2)<br>* Other names: fludarabine monophosphate;Drug: Melphalan<br>* Melphalan (50 mg/m2) in Arm A; Melphalan (100 mg/m2) in Arm B<br>* Other names: Melphalanum;Device: CliniMACS CD34 Reagent System<br>* 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<br>Drug: Tacrolimus<br>* 4-6ng/mL<br>* Other names: fujimycin;Drug: Cyclophosphamide<br>* 40mg/kg<br>* Other names: alkylating agent;Drug: Plerixafor<br>* Dose 0.24 mg/kg, manufactured by Genzyme<br>* Other names: LM-3100;Drug: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent<br>* Single-use vials contain either 300 mcg or 480 mcg filgrastim at a fill volume of 1.0 mL or 1.6 mL<br>* Other names: filgrastim XM02;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the GVHD-free relapse-free survival (GRFS) post-HCT ( Arm-A) | Clinical effect will be assessed as graft vs host disease (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. The outcome will be measured in Arm A only. | 12 months | 
| Determine the overall survival (OS) post-HCT ( Arm-B) | Overall survival is measured as number of participants alive. Alive at the time of last observation will be censored. | 2 years | 
| Incidence of Grade III-IV acute GVHD | Acute GVHD will be staged and graded per Mount Sinai Acute GvHD International Consortium (MAGIC) Standardization criteria. | At baseline, day +30, 60, 90, 180, year 1 and year 2 | 
| The incidence and timing of primary graft failure | Primary graft failure is defined as being alive with donor CD3 chimerism <5% at day +30 after transplant without recovery of neutrophils (i.e. without achieving an absolute neutrophil count [ANC] ≥ 500/mm3 for 3 consecutive days) at Day+28 | 2 years from the Day 0 (day of CD34+ peripheral blood stem cell infusion | 
| Donor CD3 chimerism at Day+60 post-HCT | Defined as a percentage on donor CD3 cells chimerism at day +60 after transplantation. | 2 years from the Day 0 (day of CD34+ peripheral blood stem cell infusion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GVHD-relapse-free survival | Clinical effect will be assessed as graft vs host disease (GVHD)-free relapse free survival (GRFS), GVHD-free is defined as no GVHD grade 3 and 4, and relapse free survival is defined as survival at 12 months without relapse. | 12 months | 
| Overall survival | Overall survival is measured as number of participants alive. Alive at the time of last observation will be censored. | 12 months | 
| Secondary graft failure | Secondary graft failure (defined by donor CD3 chimerism <5% at day +30 after transplant) and neutrophil engraftment followed by subsequent decline in ANC < 500/mm3 unresponsive to growth factor therapy, by Day +100 | from Day 0 through 100 days | 
| Treatment-emergent adverse events (TEAs) | TEAEs will be categorized by the System Organ Class and preferred term and will be graded according to the CTCAE version 5.0 | from Day 0 through 100 days | 
| Acute GVHD (all grades) | Acute GVHD (all grades) will be reported | from Day 0 through 100 days | 
| Steroid-refractory acute GVHD | Steroid refractory acute GVHD will be defined as per the EBMT-NIH-CIBMTR Task Force position statement | within 3-5 days of therapy onset | 
| Non-relapse mortality (NRM) | Non-relapse mortality is measured as number of participants died without relapse/ recurrent disease. Subjects without evidence of relapse/progression at last follow-up date or date of death will be censored. | 12 months | 
| Disease-free survival (DFS) | Overall survival is measured as number of participants alive and in remission. Alive in remission at the time of last observation will be censored. | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Reduced intensity conditioning (RIC), GVHD