Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells

NCT ID: NCT01050764

Last Updated: 2018-06-27

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-06-30
• Study Completion Date: 2014-06-30

Brief Summary

Patients with hematologic malignancies will receive myeloablative chemotherapy followed by stem cell rescue with bone marrow or hematopoietic peripheral blood stem cells collected by apheresis from a filgrastim- (G-CSF)-mobilized haploidentical related-donor, ie, hematopoietic peripheral blood stem cell transplant (HSCT).

Detailed Description

This is dose-escalation study intended to evaluate the use of classification determinant 15-positive (CD15+), CD4+, CD127dim, and FoxP3+ regulatory T-cells (T-reg cells) supplemented by conventional T-cells (T-con cells), to enhance the efficacy of allogeneic (CliniMACS CD34+ selected) hematopoietic stem cell transplantation (allo-HSCT), in the setting of leukemia, lymphoma, and myelodysplastic syndrome (MDS). This study investigates amelioration of the impaired immune recovery and address the significant relapse incidence in the haploidentical HSCT setting.

Pre-transplant myeloablative conditioning will be melphalan; thiotepa; fludarabine and rabbit antithymocyte globulin (rATG).

Stem cell rescue will be with CD34+ selected cells. The rescue infusion will be supplemented with infusions of regulatory T-cells (T-reg) and conventional T-cells (T-con) from the same donor collection, on Treatment Days 14 and 16 respectively. CD34+ cell infusion day is Treatment Day 0.

T-reg cells are those cells enriched by immunomagnetic selection of CD25+ cells, and further purified by flow cytometric cell sorting for the CD15+, CD4+, CD127dim, FoxP3+ cell population. These cells are an enriched but naturally-occurring T-cell population.

T-con cells are unseparated/unfractionated cells, ie, as collected by the peripheral blood stem cells apheresis procedure.

Post-transplant follow-up is for 5 years.

Conditions

Leukemia, Acute; Chronic Myelogenous Leukemia (CML); Myelodysplastic Syndrome (MDS); Non-Hodgkin Lymphoma (NHL); Chronic Lymphocytic Leukemia (CLL); Acute Myelogenous Leukemia (AML); Acute Lymphoblastic Leukemia (ALL)

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

T-reg Cell Infusion after Allogeneic Stem Cell Transplant

Group Type: EXPERIMENTAL

Regulatory T-cells

Intervention Type: DRUG

To ameliorate the impaired immune recovery and address the significant relapse incidence in the haploidentical setting. Cells will be selected by a tandem selection process and infused on day +14. These are the enriched but naturally-occurring regulatory T cells. Possible dose cohorts and levels are:

Cohort 1

• T-reg: 1 x 10e5/kg
• T-con: 3 x10e5/kg

Cohort 2

• T-reg: 3 x 10e5/kg
• T-con: 1 x 10e6/kg

Cohort 3

• T-reg: 1 x 10e6/kg
• T-con: 3 x 10e6/kg

Cohort 4

• T-reg: 3 x 10e6/kg
• T-con: 1 x 10e7/kg

Conventional T-cells

Intervention Type: DRUG

These are conventional (unselected) donor T-cells. Cell dosage of the infusion will be based on the CD3+ cell content and infused on day +16.

Melphalan

Intervention Type: DRUG

Anti-cancer chemotherapy drug administered IV at 140 mg/m² on Day -8 prior to HSCT (a component of the conditioning regiment prior to infusion of cells)

Thiotepa

Intervention Type: DRUG

Anti-cancer chemotherapy drug administered IV at 10 mg/kg on Day -7 prior to HSCT (a component of the conditioning regiment prior to infusion of cells)

Fludarabine

Intervention Type: DEVICE

Anti-cancer chemotherapy drug administered IV at 160mg/m² on Days -6; -5; -4; and -3 prior to HSCT (a component of the conditioning regiment prior to infusion of cells

Anti-thymocyte globulin, rabbit

Intervention Type: DRUG

Rabbit-derived antibodies against human T-cells used as transplant rejection prophylaxis. Administered at 6 mg/kg IV on Days -6; -5; -4; and -3 prior to HSCT

CliniMACS CD34 Reagent System

Intervention Type: DRUG

An in vitro medical device system that uses antibodies conjugated to magnetic beads to select and enrich for CD34+ blood stem cells from the allogeneic donor apheresis product prior to HSCT, while removing other cells that can cause GvHD. CD34+ cell dosage will be based on the participant's body weight.

Interventions

Regulatory T-cells

To ameliorate the impaired immune recovery and address the significant relapse incidence in the haploidentical setting. Cells will be selected by a tandem selection process and infused on day +14. These are the enriched but naturally-occurring regulatory T cells. Possible dose cohorts and levels are:

Cohort 1

• T-reg: 1 x 10e5/kg
• T-con: 3 x10e5/kg

Cohort 2

• T-reg: 3 x 10e5/kg
• T-con: 1 x 10e6/kg

Cohort 3

• T-reg: 1 x 10e6/kg
• T-con: 3 x 10e6/kg

Cohort 4

• T-reg: 3 x 10e6/kg
• T-con: 1 x 10e7/kg

Intervention Type: DRUG

Conventional T-cells

These are conventional (unselected) donor T-cells. Cell dosage of the infusion will be based on the CD3+ cell content and infused on day +16.

Intervention Type: DRUG

Melphalan

Anti-cancer chemotherapy drug administered IV at 140 mg/m² on Day -8 prior to HSCT (a component of the conditioning regiment prior to infusion of cells)

Intervention Type: DRUG

Thiotepa

Anti-cancer chemotherapy drug administered IV at 10 mg/kg on Day -7 prior to HSCT (a component of the conditioning regiment prior to infusion of cells)

Intervention Type: DRUG

Fludarabine

Anti-cancer chemotherapy drug administered IV at 160mg/m² on Days -6; -5; -4; and -3 prior to HSCT (a component of the conditioning regiment prior to infusion of cells

Intervention Type: DEVICE

Anti-thymocyte globulin, rabbit

Rabbit-derived antibodies against human T-cells used as transplant rejection prophylaxis. Administered at 6 mg/kg IV on Days -6; -5; -4; and -3 prior to HSCT

Intervention Type: DRUG

CliniMACS CD34 Reagent System

An in vitro medical device system that uses antibodies conjugated to magnetic beads to select and enrich for CD34+ blood stem cells from the allogeneic donor apheresis product prior to HSCT, while removing other cells that can cause GvHD. CD34+ cell dosage will be based on the participant's body weight.

Intervention Type: DRUG

Other Intervention Names

T-reg cells; T-con cells; L-PAM; L-Sarcolysin; Phenylalanine Mustard; thiophosphamide; TESPA; TSPA; Fludarabine phosphate; Fludarabine 5'-monophosphate; FAMP; Fludara; Thymoglobulin; rATG

Eligibility Criteria

Inclusion Criteria

RECIPIENT

• Histopathologically-confirmed:
• Acute leukemia (in first remission with poor risk factors and molecular prognosis)
• Acute myelogenous leukemia (AML) with -5,-7, t (6;9), tri8, -11
• Acute lymphoblastic leukemia (ALL) with Ph+ t (9;22), t (4;22), (q34;q11)
• Acute leukemia with refractory disease or > Complete Remission (CR) 1
• Chronic myelogenous leukemia (CML) (accelerated, blast or second chronic phase)
• Myelodysplastic syndrome (in high and high intermediate risk categories)
• Non-Hodgkin's lymphoma (NHL) with poor risk features and not suitable for autologous transplantation
• Refractory Chronic lymphocytic leukemia (CLL)
• At least 21 days from the end of most recent prior therapy to start of the transplant conditioning regimen
• Must be < 60 years old at time of registration.
• Karnofsky Performance Status (KPS) > 70%

Must have related donor who is:

• Genotypically human leukocyte antigen (HLA) -A, B,C and DR beta 1 (DRB1), DQ loci haploidentical to the recipient (but differing for 2 to 3 HLA alleles on the unshared haplotype in the graft-versus-host disease (GvHD) direction)
• No HLA-matched sibling or matched-unrelated donor is identified.
• Adequate cardiac and pulmonary function (left ventricular ejection fraction (LVEF) > 45%, diffusing capacity of the lungs for carbon monoxide (DLCO) >50% corrected for hemoglobin)
• Serum creatinine < 1.5 mg/dL OR Creatinine clearance > 50 mL/min for those above serum creatinine at least 1.5 mg/dL
• Serum bilirubin < 2.0 mg/dL
• Alanine transaminase (ALT) < 2x upper normal limit (ULN) (unless secondary to disease)
• No prior myeloablative therapy or hematopoietic cell transplantation

DONOR:

• Age ≤ 70 years
• Weight ≥ 25 kg.
• Medical history and physical examination confirm good health status as defined by institutional standards
• Seronegative for HIV Ag within 30 days of apheresis collection for:
• Hepatitis B surface antigen (sAg) or polymerase chain reaction (PCR) +
• Hepatitis C ab or PCR+
• Genotypically haploidentical as determined by HLA typing
• Female donors (child-bearing potential) must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test within 3 weeks of mobilization
• Capable of undergoing leukapheresis
• Has adequate venous access
• Willing to undergo insertion of a central catheter if leukapheresis via peripheral vein is inadequate
• Capable of agreeing to second donation of peripheral blood progenitor cell (PBPC) (or a bone marrow harvest) should the patient fail to demonstrate sustained engraftment following the transplant
• Institutional review board (IRB)-approved consent form signed by donor or legal guardian > 18 years of age

Donor Selection in the priority order:

• Recipient's biological mother preferred, if available
• Other available haploidentical donors will be selected based upon the presence of natural killer (NK) alloreactivity between donor and recipient by high-resolution HLA typing of the C locus. An NK-alloreactive donor will be preferentially chosen. Recipients lacking a killer immunoglobulin-like receptor (KIR)-ligand present in the donor along with the corresponding KIR defines "NK alloreactivity".
• If more than one NK-alloreactive donor is available, preference is to cytomegalovirus (CMV)-seronegative donor

Exclusion Criteria

RECIPIENT:

• Suitable candidate for autologous transplantation or allogeneic transplantation with an available matched-related or matched-unrelated donor
• Seropositive for:
• HIV ab
• Hepatitis B sAg or PCR+
• Hepatitis C ab or PCR+
• History of invasive Aspergillosis
• Any active, uncontrolled bacterial, viral or fungal infection
• Uncontrolled central nervous system (CNS) disease involvement
• Lactating female

DONOR:

• Evidence of active infection or viral hepatitis
• Factors of increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy
• Lactating female
• HIV-positive

• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Doris Duke Charitable Foundation

OTHER

Sponsor Role: collaborator

Everett Meyer

OTHER

Sponsor Role: lead

Responsible Party

Everett Meyer

Assistant Professor of Medicine (Blood and Marrow Transplantation)

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Everett H Meyer, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Locations

Stanford University School of Medicine

Stanford, California, United States

Countries

United States

Other Identifiers

BMT204

Identifier Type: OTHER

Identifier Source: secondary_id

SU-03312009-2059

Identifier Type: OTHER

Identifier Source: secondary_id

IRB-15919

Identifier Type: -

Identifier Source: org_study_id