Haploidentical Donor Hematopoietic Progenitor Cell and NK Cell Transplantation for Hematologic Malignancy

Sponsor

St. Jude Children's Research Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT01807611

Collaborator

Assisi Foundation (Other)

162

Enrollment

Location

Arm

100.4

Actual Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In this study, participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT), who do not have a suitable human leukocyte antigen (HLA) matched related/sibling donor (MSD) or matched unrelated donor (MUD) identified, will receive a haploidentical donor HCT with additional natural killer (NK) cells.

The investigators anticipate enrollment of 75 donors and 75 recipients.

PRIMARY OBJECTIVE:

To estimate the rate of successful engraftment at day +42 post-transplant in patients who receive haploidentical donor stem cell plus NK cell transplantation with TLI based conditioning regimen for high risk hematologic malignancy.

SECONDARY OBJECTIVES:

Estimate the incidence of malignant relapse, event-free survival, and overall survival at one-year post-transplantation.
Estimate incidence and severity of acute and chronic (GVHD).
Estimate the rate of transplant related mortality (TRM) in the first 100 days after transplantation.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Lymphoma	Radiation: Total Lymphoid Irradiation Drug: Fludarabine Drug: Cyclophosphamide Drug: Thiotepa Drug: Melphalan Biological: HPC,A Infusion Biological: TC-NK Infusion Biological: G-CSF Drug: Mesna Device: CliniMACS Drug: Mycophenolate mofetil	Phase 2

Detailed Description

Donors will undergo G-CSF mobilization of peripheral blood stem cells (PBSC) prior to undergoing two apheresis collections of hematopoietic progenitor cells (HPC,A) and one apheresis collection of therapeutic cell product of purified natural killer cells (TC-NK).

The HPC products will be T-cell depleted (TCD) using the investigational CliniMACS device. CD34+ enrichment and CD45RA depletion will be utilized on sequential HPC grafts.

Participants will undergo a preparative regimen of total lymphoid irradiation, fludarabine, cyclophosphamide, granulocyte colony stimulating factor (G-CSF), thiotepa, and melphalan. This is followed by infusions of donor cells that have been prepared using the CliniMACS system: HPC,A (CD34+ selected), HPC,A (CD45RA depleted), and TC-NK.

Study Design

Study Type:

Interventional

Actual Enrollment :

162 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Haploidentical Donor Hematopoietic Progenitor Cell and Natural Killer Cell Transplantation With a TLI Based Conditioning Regimen in Patients With Hematologic Malignancies

Actual Study Start Date :

May 16, 2013

Actual Primary Completion Date :

Aug 27, 2021

Actual Study Completion Date :

Sep 27, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Transplant Recipients Participants undergo a preparative regimen of total lymphoid irradiation, fludarabine, cyclophosphamide, fludarabine, thiotepa, melphalan, and mycophenolate mofetil, followed by HPC,A infusion and TC-NK infusion. They also receive G-CSF and mesna. Cells for infusion are prepared using the CliniMACS System.	Radiation: Total Lymphoid Irradiation Participants receive total lymphoid irradiation over four doses. Other Names: TLI Drug: Fludarabine Given IV. Other Names: Fludara Drug: Cyclophosphamide Given IV. Other Names: Cytoxan Drug: Thiotepa Given IV. Other Names: Thioplex(R) by Immunex TESPA TSPA Drug: Melphalan Given IV. Other Names: L-phenylalanine mustard Phenylalanine Mustard L-PAM L-sarcolysin Alkeran(R) Biological: HPC,A Infusion Participants received infusions of HPC,A (CD34+ selected) and HPC,A (CD45RA depleted). Biological: TC-NK Infusion Participants receive infusions of TC-NK. Biological: G-CSF Participants receive G-CSF subcutaneously or intravenously. Donors receive G-CSF subcutaneously during cell mobilization. Other Names: Granulocyte Colony-Stimulating Factor Filgrastim Neupogen(R) Drug: Mesna Mesna is generally dosed at approximately 25% of the cyclophosphamide dose. It is generally given intravenously prior to and again at 3, 6 and 9 hours following each dose of cyclophosphamide. Other Names: Mesnex Device: CliniMACS The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells. Other Names: Cell Selection System Drug: Mycophenolate mofetil Given intravenously or orally. Other Names: MMF CellCept®

Arm

Intervention/Treatment

Experimental: Transplant Recipients

Participants undergo a preparative regimen of total lymphoid irradiation, fludarabine, cyclophosphamide, fludarabine, thiotepa, melphalan, and mycophenolate mofetil, followed by HPC,A infusion and TC-NK infusion. They also receive G-CSF and mesna. Cells for infusion are prepared using the CliniMACS System.

Radiation: Total Lymphoid Irradiation

Participants receive total lymphoid irradiation over four doses.

Other Names:

TLI

Drug: Fludarabine

Given IV.

Other Names:

Fludara

Drug: Cyclophosphamide

Given IV.

Other Names:

Cytoxan

Drug: Thiotepa

Given IV.

Other Names:

Thioplex(R) by Immunex

TESPA

TSPA

Drug: Melphalan

Given IV.

Other Names:

L-phenylalanine mustard

Phenylalanine Mustard

L-PAM

L-sarcolysin

Alkeran(R)

Biological: HPC,A Infusion

Participants received infusions of HPC,A (CD34+ selected) and HPC,A (CD45RA depleted).

Biological: TC-NK Infusion

Participants receive infusions of TC-NK.

Biological: G-CSF

Participants receive G-CSF subcutaneously or intravenously. Donors receive G-CSF subcutaneously during cell mobilization.

Other Names:

Granulocyte Colony-Stimulating Factor

Filgrastim

Neupogen(R)

Drug: Mesna

Mesna is generally dosed at approximately 25% of the cyclophosphamide dose. It is generally given intravenously prior to and again at 3, 6 and 9 hours following each dose of cyclophosphamide.

Other Names:

Mesnex

Device: CliniMACS

The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.

Other Names:

Cell Selection System

Drug: Mycophenolate mofetil

Given intravenously or orally.

Other Names:

MMF

CellCept®

Outcome Measures

Primary Outcome Measures

Rate of successful engraftment [42 days post engraftment]
Neutrophil engraftment will be determined using the parameters put forth by the Center for International Blood and Marrow Registry. Assessments will be made upon review of daily complete blood count and serial chimerism studies. Successful engraftment for the purposes of this objective will be patients who do not experience graft failure.

Secondary Outcome Measures

Incidence of malignant relapse [one year post-transplantation.]
Bone marrow studies for disease status evaluation will be performed at approximately 21 days, 100 days, and 1 year post-transplant. Testing will include a research evaluation for minimal residual disease.
Event-free survival [One year post-transplantation]
Overall survival [one year post-transplantation]
Incidence of acute and chronic graft versus host disease (GVHD) [100 days post-transplant]
Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The cumulative incidence of acute and chronic GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The analysis for this objective will be performed when the last evaluable participant has been followed for 100 days post transplant.
Rate of transplant-related mortality (TRM) [in the first 100 days after transplantation]
Severity of acute and chronic graft versus host disease (GVHD) [100 days post-transplant]
Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The severity of acute GvHD and chronic GvHD will be described. The analysis for this objective will be performed when the last evaluable participant has been followed for 100 days post transplant.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria - Transplant Recipients:

Age less than or equal to 21 years.
Does not have a suitable MSD or volunteer MUD available in the necessary time for stem cell donation.
Has a suitable single haplotype matched (≥ 3 of 6) and family member donor.
High risk hematologic malignancy.
If prior CNS leukemia, it must be treated and in CNS CR
Does not have any other active malignancy other than the one for which this HCT is indicated.
No prior allogeneic HCT, and no autologous HCT within the previous 12 months.
Patient must fulfill pre-transplant evaluation

Inclusion Criteria - Haploidentical Donor:

At least single haplotype matched (≥ 3 of 6) family member
At least 18 years of age.
HIV negative.
Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).
Not breast feeding.
Regarding eligibility, is identified as either: (1) Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR (2) Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 CFR