T-Cell Replete Haploidentical Donor Hematopoietic Stem Cell Plus Natural Killer (NK) Cell Transplantation in Patients With Hematologic Malignancies Relapsed or Refractory Despite Previous Allogeneic Transplant
Primary Purpose
Acute Lymphoblastic Leukemia, Acute Myelocytic Leukemia, Chronic Myelocytic Leukemia
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
clofarabine
cytarabine
busulfan
Plerixafor
cyclophosphamide
antithymocyte globulin (rabbit)
stem cells
Tacrolimus
mycophenolate mofetil
Sponsored by
About this trial
This is an interventional treatment trial for Acute Lymphoblastic Leukemia focused on measuring Hematologic malignancy, Hematopoietic cell transplant
Eligibility Criteria
Inclusion Criteria - for transplant recipient:
- Age less than 21 years.
One of the following hematologic malignancies that has relapsed or remains refractory after prior allogeneic HCT:
- Acute lymphoblastic leukemia (ALL)
- Acute myeloid leukemia (AML) (including myeloid sarcoma)
- Chronic myelogenous leukemia (CML), juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), Hodgkin or 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 have no evidence of CNS disease
- Does not have current uncontrolled bacterial, fungal, or viral infection per the judgment of the principal investigator.
Patient must fulfill pre-transplant evaluation:
- Left ventricular ejection fraction greater than 40%, or shortening fraction greater than or equal to 25%.
- Creatinine clearance or Glomerular Filtration Rate of ≥70 ml/min/1.73m^2.
- 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.
- Total bilirubin ≤ 1.5 times the upper limit of normal for age.
- Alanine aminotransferase (ALT) ≤ 3 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.
- Does not have active acute bronchiolitis obliterans or bronchiolitis obliterans organizing pneumonia.
Inclusion Criteria - for donor:
- At least single haplotype matched (≥ 3 of 6) family member,
- At least 18 years of age.
- Human immunodeficiency virus (HIV) negative.
- Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).
- Not breast feeding.
A suitable donor is identified as either:
- Has 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.
Exclusion Criteria:
- Does not meet above inclusion criteria.
Sites / Locations
- St. Jude Children's Research Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment
Arm Description
All study participants. Interventions: clofarabine, cytarabine, busulfan, plerixafor, cyclophosphamide, antithymocyte globulin (rabbit), stem cells, tacrolimus, mycophenolate mofetil
Outcomes
Primary Outcome Measures
One-year Survival (OS)
Evaluate the number of participants alive at 1 year. The number of participants surviving to one-year post-transplantation is given.
Secondary Outcome Measures
Incidence of Malignant Relapse
Estimate the incidence of malignant relapse at one year post-transplant. The number of participants with malignant relapse or progressive disease is given. Relapse was evaluated using standard WHO criteria for each disease.
Event-Free Survival (EFS)
Estimate the EFS at one-year post-transplantation. The event is defined as relapse or death due to any cause. The number of participants who were alive without relapse at one year post-transplant is reported.
Disease-Free Survival (DFS)
Estimate the DFS at one-year post-transplantation. The event is defined as relapse or death due to relapse. The number of participants who did not relapse up to one year post transplant is reported.
Incidence and Severity of Acute Graft Versus Host Disease (GVHD)
The number of participants with acute GVHD is given, organized by grade. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe.
Incidence and Severity of Chronic Graft Versus Host Disease (GVHD)
The severity of chronic GVHD will be described. Chronic GVHD was evaluated using NIH Consensus Global Severity Scoring. The number of participants with chronic GVHD is given, organized by severity.
Number of Participants With Transplant Related Mortality (TRM)
The number of participants who died due to TRM in the first 100 days post-transplant is given.
Full Information
NCT ID
NCT01621477
First Posted
June 8, 2012
Last Updated
December 28, 2016
Sponsor
St. Jude Children's Research Hospital
Collaborators
Assisi Foundation
1. Study Identification
Unique Protocol Identification Number
NCT01621477
Brief Title
T-Cell Replete Haploidentical Donor Hematopoietic Stem Cell Plus Natural Killer (NK) Cell Transplantation in Patients With Hematologic Malignancies Relapsed or Refractory Despite Previous Allogeneic Transplant
Official Title
T-Cell Replete Haploidentical Donor Hematopoietic Stem Cell Plus Natural Killer (NK) Cell Transplantation in Patients With Hematologic Malignancies Relapsed or Refractory Despite Previous Allogeneic Transplant
Study Type
Interventional
2. Study Status
Record Verification Date
December 2016
Overall Recruitment Status
Terminated
Why Stopped
Study was terminated in August 2016 due to replacement by a new study.
Study Start Date
August 2012 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
December 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
St. Jude Children's Research Hospital
Collaborators
Assisi Foundation
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The primary aim of this protocol is to evaluate if the one-year survival is significantly improved in the group of patients who receive a T-cell replete haploidentical donor hematopoietic cell transplant (HCT) with a novel reduced intensity conditioning regimen. Study population will consist of patients (21 years or under) with hematologic malignancies that have relapsed or are refractory after prior allogeneic transplant. Toxicity will be evaluated by the rate of transplant related mortality and the rates of moderate and severe graft-versus-host disease (GvHD) at day 100. The investigators will describe event-free, and disease-free survival at one year, as well as the rates of hematopoietic recovery and donor engraftment and study comprehensively immune reconstitution following T-cell replete haploidentical transplantation.
Detailed Description
Patients with refractory hematologic malignancies, including those who develop recurrent disease after allogeneic hematopoietic cell transplantation, have a dismal prognosis. Historically, both regimen-related mortality and disease recurrence have been significant causes of treatment failure in this heavily pre-treated patient population. Our institution has utilized mismatched family member (haploidentical) donors for these patients for a number of years for the following reasons: (1) Only 30% of patients have matched related donors available; (2) transplantation can be performed more rapidly since the time to unrelated donor transplantation averages 3 to 4 months; (3) no other curative treatment options are available. These therapeutic interventions have been largely successful given the dismal prognosis in this patient group; however disease recurrence remains the most significant cause of treatment failure. To provide maximum benefit for this challenging population, the goals of a therapeutic transplant protocol should include: (1) a conditioning regimen that is well tolerated, even in a heavily pre-treated population; but it should also provide substantial antileukemia effects, and (2) should establish rapid immune recovery such that the patient may benefit from graft versus leukemia effect and early protection from life threatening infections while also limiting dangerous and counter-productive graft versus host disease.
The primary aim of this protocol will be to evaluate if the one-year survival is significantly improved in the group of patients receiving T-cell replete haploidentical donor HCT with a novel clofarabine, cytarabine, busulfan, plerixafor, cyclophosphamide, and ATG based reduced intensity conditioning regimen whose hematologic malignancy has relapsed or is refractory after prior allogeneic transplant. Toxicity will be evaluated by the rate of transplant related mortality and the rates of moderate and severe graft versus host disease at day 100. The investigators will also describe event-free, and disease-free survival at one year, as well as the rates of hematopoietic recovery and donor engraftment. Additionally, the investigators will study comprehensively immune reconstitution following T-cell replete haploidentical transplantation.
PRIMARY OBJECTIVE:
Evaluate if the one-year survival is significantly improved in a group of children receiving a therapeutic regimen for high-risk hematologic malignancy that is relapsed or refractory despite previous allogeneic hematopoietic cell transplantation (HCT) using a novel reduced intensity conditioning and T-cell replete haploidentical donor hematopoietic stem cell plus NK cell transplantation.
SECONDARY OBJECTIVES:
Estimate the incidence of malignant relapse, event-free survival, and disease free survival (DFS) 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia, Acute Myelocytic Leukemia, Chronic Myelocytic Leukemia, Juvenile Myelomonocytic Leukemia, Myelodysplastic Syndrome, Hodgkin or Non-Hodgkin Lymphoma, Sarcoma, Myeloid
Keywords
Hematologic malignancy, Hematopoietic cell transplant
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
34 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment
Arm Type
Experimental
Arm Description
All study participants.
Interventions: clofarabine, cytarabine, busulfan, plerixafor, cyclophosphamide, antithymocyte globulin (rabbit), stem cells, tacrolimus, mycophenolate mofetil
Intervention Type
Drug
Intervention Name(s)
clofarabine
Other Intervention Name(s)
Cl-F-Ara-A, CAFdA, Clofarex, Clolar(TM)
Intervention Description
Given on Day -9 and Day -8 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
Intervention Type
Drug
Intervention Name(s)
cytarabine
Other Intervention Name(s)
Ara-C
Intervention Description
Given on Day -9 and Day -8 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
Intervention Type
Drug
Intervention Name(s)
busulfan
Other Intervention Name(s)
Myleran(R), Busulfex
Intervention Description
Given on Day -7 and Day -6 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
Intervention Type
Drug
Intervention Name(s)
Plerixafor
Other Intervention Name(s)
AMD3100, Mozobil(R)
Intervention Description
Given on Day -7 and Day -6 (Day 0 is first stem cell infusion). Drug class: Hematopoietic Stem Cell Mobilizer
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Given on Day -5 and Day +4 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent; immunosuppressive agent.
Intervention Type
Drug
Intervention Name(s)
antithymocyte globulin (rabbit)
Other Intervention Name(s)
Rabbit ATG, Rabbit Thymoglobulin(R)
Intervention Description
Given on Day -4, Day -3, Day -2, and Day -1 (Day 0 is first stem cell infusion). Drug class: immunosuppressive agent.
Intervention Type
Biological
Intervention Name(s)
stem cells
Other Intervention Name(s)
HSC infusion
Intervention Description
Patients undergo T cell replete Hematopoietic stem cell infusion on Day 0 and Day +1. Patients undergo natural killer (NK) cell transplantation on day +6 (Day 0 is first stem cell infusion).
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
FK506, Prograf(R), Protonic(R)
Intervention Description
Given on Day +11 (Day 0 is first stem cell infusion). Drug class: immunosuppressive agent.
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Other Intervention Name(s)
MMF, CellCept(R)
Intervention Description
Given on Day +11 (Day 0 is first stem cell infusion). Drug class: immunosuppressive agent.
Primary Outcome Measure Information:
Title
One-year Survival (OS)
Description
Evaluate the number of participants alive at 1 year. The number of participants surviving to one-year post-transplantation is given.
Time Frame
One year post transplant
Secondary Outcome Measure Information:
Title
Incidence of Malignant Relapse
Description
Estimate the incidence of malignant relapse at one year post-transplant. The number of participants with malignant relapse or progressive disease is given. Relapse was evaluated using standard WHO criteria for each disease.
Time Frame
One year post transplantation.
Title
Event-Free Survival (EFS)
Description
Estimate the EFS at one-year post-transplantation. The event is defined as relapse or death due to any cause. The number of participants who were alive without relapse at one year post-transplant is reported.
Time Frame
one year post transplant
Title
Disease-Free Survival (DFS)
Description
Estimate the DFS at one-year post-transplantation. The event is defined as relapse or death due to relapse. The number of participants who did not relapse up to one year post transplant is reported.
Time Frame
one year post transplant
Title
Incidence and Severity of Acute Graft Versus Host Disease (GVHD)
Description
The number of participants with acute GVHD is given, organized by grade. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe.
Time Frame
100 days post transplant
Title
Incidence and Severity of Chronic Graft Versus Host Disease (GVHD)
Description
The severity of chronic GVHD will be described. Chronic GVHD was evaluated using NIH Consensus Global Severity Scoring. The number of participants with chronic GVHD is given, organized by severity.
Time Frame
100 days post transplant
Title
Number of Participants With Transplant Related Mortality (TRM)
Description
The number of participants who died due to TRM in the first 100 days post-transplant is given.
Time Frame
100 days post transplant
10. Eligibility
Sex
All
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria - for transplant recipient:
Age less than 21 years.
One of the following hematologic malignancies that has relapsed or remains refractory after prior allogeneic HCT:
Acute lymphoblastic leukemia (ALL)
Acute myeloid leukemia (AML) (including myeloid sarcoma)
Chronic myelogenous leukemia (CML), juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), Hodgkin or 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 have no evidence of CNS disease
Does not have current uncontrolled bacterial, fungal, or viral infection per the judgment of the principal investigator.
Patient must fulfill pre-transplant evaluation:
Left ventricular ejection fraction greater than 40%, or shortening fraction greater than or equal to 25%.
Creatinine clearance or Glomerular Filtration Rate of ≥70 ml/min/1.73m^2.
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.
Total bilirubin ≤ 1.5 times the upper limit of normal for age.
Alanine aminotransferase (ALT) ≤ 3 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.
Does not have active acute bronchiolitis obliterans or bronchiolitis obliterans organizing pneumonia.
Inclusion Criteria - for donor:
At least single haplotype matched (≥ 3 of 6) family member,
At least 18 years of age.
Human immunodeficiency virus (HIV) negative.
Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).
Not breast feeding.
A suitable donor is identified as either:
Has 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.
Exclusion Criteria:
Does not meet above inclusion criteria.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brandon M. 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
T-Cell Replete Haploidentical Donor Hematopoietic Stem Cell Plus Natural Killer (NK) Cell Transplantation in Patients With Hematologic Malignancies Relapsed or Refractory Despite Previous Allogeneic Transplant
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