Clinical trial NCT01050764: Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells
Official title: A Feasibility Trial of Post-Transplant Infusion of Allogeneic Regulatory T Cells and Allogeneic Conventional T Cells in Patients With Hematologic Malignancies Undergoing Allogeneic Myeloablative Hematopoietic Cell Transplantation From Haploidentical-Related Donors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
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)
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: Doris Duke Charitable Foundation
First posted: 2010-01-15
Enrollment: 10
Sex: ALL
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Maximum-tolerated Dose (MTD) of Regulatory and Conventional T-cells
timeFrame: 30 days after HSCT infusion
Secondary outcomes:
measure: Acute Graft-versus-Host-Disease (aGvHD)
timeFrame: 1 year
measure: Overall Survival (OS), 1 Year
timeFrame: 1 year
measure: Median Overall Survival (OS)
timeFrame: 25 months
measure: To Measure the Incidence and Severity of Acute and Chronic GvHD
timeFrame: 1 year
measure: Serious Infections
timeFrame: 1 year
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
Study officials:
affiliation: Stanford University
name: Everett H Meyer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: