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Repeat Transplantation for Relapsed or Refractory Hematologic Malignancies Following Prior Transplantation

Primary Purpose

Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Myeloid Sarcoma

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cyclophosphamide
Fludarabine
G-CSF
Interleukin-2
Melphalan
Thiotepa
Rituximab
Natural killer cell therapy
T-cell depleted HPC transplant
CD45RA-depleted HPC transplant
Sponsored by
St. Jude Children's Research Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia (ALL) focused on measuring Hematological malignancies, Allogeneic hematopoietic cell transplant, Refractory hematologic malignancy, Relapsed hematologic malignancy

Eligibility Criteria

undefined - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age less than or equal to 21 years.

  • One of the following hematologic malignancies that has relapsed or remains refractory after prior allogeneic hematopoietic cell transplant (HCT):

    • ALL, AML, Myeloid Sarcoma, CML, Juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL)
  • Has a suitable single haplotype matched (≥ 3 of 6) family member donor.
  • Does not have any other active malignancy other than the one for which this transplant is indicated.
  • If prior central nervous system (CNS) leukemia, it must be treated and in CNS complete remission (CR)
  • Does not have current uncontrolled bacterial, fungal, or viral infection.
  • Patient must fulfill pre-transplant evaluation:
  • Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%.
  • Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2.
  • Forced vital capacity (FVC) ≥ 40% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing.
  • Karnofsky or Lansky (age-dependent) performance score ≥ 50 (See Appendix A).
  • Bilirubin ≤ 3 times the upper limit of normal for age.
  • Alanine aminotransferase (ALT) ≤ 5 times the upper limit of normal for age.
  • Not pregnant. If female with child bearing potential, must be confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment.
  • Not breast feeding
  • DONOR: At least single haplotype matched (≥ 3 of 6) family member
  • DONOR: At least 18 years of age.
  • DONOR: HIV negative.
  • DONOR: Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).
  • DONOR: Not breast feeding.

  • DONOR: Regarding donation eligibility, is identified as either:

    • Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR
    • 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 1271.

Sites / Locations

  • St. Jude Children's Research Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Participants

Arm Description

Participants undergo a conditioning regimen with cyclophosphamide, fludarabine, aldesleukin (interleukin-2), natural killer cell therapy, anti-thymocyte globulin, rituximab, thiotepa, and melphalan prior to transplantation of T-cell depleted HPC transplant on day 0 and CD45RA-depleted HPC transplant on day 1. Beginning Day 6 post-transplant, patients receive G-CSF daily until ANC recovers to normal level.

Outcomes

Primary Outcome Measures

Percentage of Participants Engrafted by Day 42 Post-transplant
To estimate engraftment by day +42 post-transplant in patients who receive CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen that includes haploidentical NK cells. Engraftment is defined as the first of 3 consecutive tests performed on different days of an ANC ≥ 500/mm^3 with evidence of donor cell engraftment.

Secondary Outcome Measures

Incidence of Malignant Relapse
The estimate of cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The number of participants with incidence of malignant relapse is given. Relapse was evaluated using standard WHO criteria for each disease.
Event-free Survival (EFS)
The Kaplan-Meier estimate of event-free survival (EFS) along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\kme) available in the Department of Biostatistics at St. Jude, where EFS = min (date of last follow-up, date of relapse, date of graft failure, date of death due to any cause) - date of transplant, and all participants surviving at the time of analysis without events will be censored. The number of participants who did not experience any of these events through one year post-transplant is given.
Overall Survival (OS)
The Kaplan-Meier estimate of OS along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\kme) available in the Department of Biostatistics at St. Jude, where OS = min (date of last follow-up, date of death) - date of transplant and all participants surviving at the time of analysis without events will be censored. The number of participants surviving to one-year post-transplantation is given.
Incidence and Severity of Acute GvHD
The cumulative incidence of acute GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of acute GvHD. The number of participants with incidence by grade is given. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe.
Incidence and Severity of Chronic GvHD
The cumulative incidence of chronic GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of chronic GvHD will be described. Chronic GvHD was evaluated using NIH Consensus Global Severity Scoring." The number of participants with incidence by severity is given.
Rate of Transplant-related Mortality (TRM)
The cumulative incidence of transplant related mortality will be estimated using Kalbfleisch-Prentice method. Deaths before day 100 because of other reasons are the competing risk events.

Full Information

First Posted
October 3, 2014
Last Updated
April 24, 2017
Sponsor
St. Jude Children's Research Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02259348
Brief Title
Repeat Transplantation for Relapsed or Refractory Hematologic Malignancies Following Prior Transplantation
Official Title
CD45A-Depleted Haploidentical Hematopoietic Progenitor Cell and Natural Killer Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
September 2016
Overall Recruitment Status
Terminated
Why Stopped
Investigator's decision.
Study Start Date
October 2014 (undefined)
Primary Completion Date
April 2015 (Actual)
Study Completion Date
March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
St. Jude Children's Research Hospital

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This pilot phase II trial studies how well a new reduced intensity conditioning regimen that includes haploidentical donor NK cells followed by the infusion of selectively T-cell depleted progenitor cell grafts work in treating younger patients with hematologic malignancies that have returned after or did not respond to treatment with a prior transplant. Giving chemotherapy and natural killer cells before a donor progenitor cell transplant may help stop the growth of cells in the bone marrow, including normal blood-forming cells (progenitor cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's cells. When the healthy progenitor cells from a related donor are infused into the patient they make red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Removing specific T cells from the donor cells before the transplant may prevent this.
Detailed Description
PRIMARY OBJECTIVE: To estimate engraftment by day +42 post-transplant in patients who receive CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen that includes haploidentical natural killer (NK) cells. 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. Blood progenitor cells will be collected from adult donors to be used for transplantation. Donor cells will be processed and filtered in a laboratory at St. Jude using a machine called the CliniMACS™ device, and later infused (transplanted) into the participant through his/her veins. Participants undergo a conditioning regimen beginning Day 21 prior to progenitor cell transplantation that includes chemotherapy medications and natural killer cells in preparation for transplantation. They will then receive T-cell depleted HPC transplant followed by CD45RA-depleted HPC transplant the following day.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Myeloid Sarcoma, Chronic Myelogenous Leukemia (CML), Juvenile Myelomonocytic Leukemia (JMML), Myelodysplastic Syndrome (MDS), Non-Hodgkin Lymphoma (NHL)
Keywords
Hematological malignancies, Allogeneic hematopoietic cell transplant, Refractory hematologic malignancy, Relapsed hematologic malignancy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Participants
Arm Type
Experimental
Arm Description
Participants undergo a conditioning regimen with cyclophosphamide, fludarabine, aldesleukin (interleukin-2), natural killer cell therapy, anti-thymocyte globulin, rituximab, thiotepa, and melphalan prior to transplantation of T-cell depleted HPC transplant on day 0 and CD45RA-depleted HPC transplant on day 1. Beginning Day 6 post-transplant, patients receive G-CSF daily until ANC recovers to normal level.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Given intravenously (IV)
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara, Fludarabine monophosphate
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
G-CSF
Other Intervention Name(s)
Filgrastim, Neupogen®
Intervention Description
Given IV or subcutaneously (SQ)
Intervention Type
Biological
Intervention Name(s)
Interleukin-2
Other Intervention Name(s)
IL-2, Aldesleukin
Intervention Description
Given SQ
Intervention Type
Drug
Intervention Name(s)
Melphalan
Other Intervention Name(s)
L-phenylalanine mustard, Phenylalanine mustard, L-PAM, L-sarcolysin, Alkeran®
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Other Intervention Name(s)
ThioplexV, TESPA, TSPA
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan™
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Natural killer cell therapy
Other Intervention Name(s)
NK cell therapy
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
T-cell depleted HPC transplant
Other Intervention Name(s)
HPC,A Infusion(ɑ/β T cell depleted)
Intervention Description
T-cell depleted hematopoietic stem cells will be infused on day 0.
Intervention Type
Biological
Intervention Name(s)
CD45RA-depleted HPC transplant
Intervention Description
CD45RA depleted stem cells will be infused on day 1.
Primary Outcome Measure Information:
Title
Percentage of Participants Engrafted by Day 42 Post-transplant
Description
To estimate engraftment by day +42 post-transplant in patients who receive CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen that includes haploidentical NK cells. Engraftment is defined as the first of 3 consecutive tests performed on different days of an ANC ≥ 500/mm^3 with evidence of donor cell engraftment.
Time Frame
Day 42 post transplantation
Secondary Outcome Measure Information:
Title
Incidence of Malignant Relapse
Description
The estimate of cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The number of participants with incidence of malignant relapse is given. Relapse was evaluated using standard WHO criteria for each disease.
Time Frame
one year post transplantation
Title
Event-free Survival (EFS)
Description
The Kaplan-Meier estimate of event-free survival (EFS) along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\kme) available in the Department of Biostatistics at St. Jude, where EFS = min (date of last follow-up, date of relapse, date of graft failure, date of death due to any cause) - date of transplant, and all participants surviving at the time of analysis without events will be censored. The number of participants who did not experience any of these events through one year post-transplant is given.
Time Frame
one year post transplantation
Title
Overall Survival (OS)
Description
The Kaplan-Meier estimate of OS along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\kme) available in the Department of Biostatistics at St. Jude, where OS = min (date of last follow-up, date of death) - date of transplant and all participants surviving at the time of analysis without events will be censored. The number of participants surviving to one-year post-transplantation is given.
Time Frame
one year post transplantation
Title
Incidence and Severity of Acute GvHD
Description
The cumulative incidence of acute GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of acute GvHD. The number of participants with incidence by grade is given. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe.
Time Frame
100 days post transplantation
Title
Incidence and Severity of Chronic GvHD
Description
The cumulative incidence of chronic GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of chronic GvHD will be described. Chronic GvHD was evaluated using NIH Consensus Global Severity Scoring." The number of participants with incidence by severity is given.
Time Frame
one year post transplantation
Title
Rate of Transplant-related Mortality (TRM)
Description
The cumulative incidence of transplant related mortality will be estimated using Kalbfleisch-Prentice method. Deaths before day 100 because of other reasons are the competing risk events.
Time Frame
100 days post transplantation

10. Eligibility

Sex
All
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age less than or equal to 21 years. One of the following hematologic malignancies that has relapsed or remains refractory after prior allogeneic hematopoietic cell transplant (HCT): ALL, AML, Myeloid Sarcoma, CML, Juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL) Has a suitable single haplotype matched (≥ 3 of 6) family member donor. Does not have any other active malignancy other than the one for which this transplant is indicated. If prior central nervous system (CNS) leukemia, it must be treated and in CNS complete remission (CR) Does not have current uncontrolled bacterial, fungal, or viral infection. Patient must fulfill pre-transplant evaluation: Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%. Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2. Forced vital capacity (FVC) ≥ 40% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing. Karnofsky or Lansky (age-dependent) performance score ≥ 50 (See Appendix A). Bilirubin ≤ 3 times the upper limit of normal for age. Alanine aminotransferase (ALT) ≤ 5 times the upper limit of normal for age. Not pregnant. If female with child bearing potential, must be confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment. Not breast feeding DONOR: At least single haplotype matched (≥ 3 of 6) family member DONOR: At least 18 years of age. DONOR: HIV negative. DONOR: Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female). DONOR: Not breast feeding. DONOR: Regarding donation eligibility, is identified as either: Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR 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 1271.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brandon Triplett, MD
Organizational Affiliation
St. Jude Children's Research Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.stjude.org
Description
St. Jude Children's Research Hospital
URL
http://www.stjude.org/protocols
Description
Clinical Trials Open at St. Jude

Learn more about this trial

Repeat Transplantation for Relapsed or Refractory Hematologic Malignancies Following Prior Transplantation

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