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Mismatched Family Member Donor Transplantation for Children and Young Adults With High Risk Hematological Malignancies

Primary Purpose

Leukemia, Acute Lymphocytic (ALL), Leukemia, Myeloid, Acute(AML), Leukemia, Myeloid, Chronic(CML)

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
CliniMACS
Stem cell transplantation
Fludarabine
Thioplex®
L-phenylalanine mustard
Mycophenolate mofetil
Rituxan™
Alemtuzumab
Cyclophosphamide
Anti-thymocyte globulin (Rabbit)
G-CSF
Muromonab
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 Leukemia, Acute Lymphocytic (ALL) focused on measuring Haploidentical stem cell transplant, Allogeneic stem cell transplant, Mismatched family member stem cell donor transplant, Bone marrow transplant, High risk hematologic malignancies, T cell depletion methodology, Miltenyi Biotec CliniMACS stem cell selection device, Campath-1H intravenous

Eligibility Criteria

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

Inclusion Criteria:(transplant recipient)

  • Patients less than or equal to 21 years of age; may be greater than 21 years old if a current St. Jude patient or previously treated St. Jude patient within 3 years of completion of prior treatment.

  • Must have one of the following diagnosis:

    • ALL high risk in second remission. Examples include relapse on therapy, first remission duration of less than or equal to 30 months, or relapse within 12 months of completing therapy.
    • ALL in third or subsequent remission.
    • ALL high risk in first remission. Examples include: induction failure, minimal residual disease greater than or equal to 1% marrow blasts by morphology after induction, persistent or recurrent cytogenetic or molecular evidence of disease during therapy requiring additional therapy after induction to achieve remission.
    • High-risk AML in first remission. Examples include monosomy 7, M6, M7, t(6;9), FLT3-ITD, or patients who have greater than or equal to 25% blasts by morphology after induction or who do not achieve CR after 2 courses of therapy (includes myeloid sarcoma).
    • Relapsed or persistent AML (less than or equal to 25% blasts in marrow by morphology).
    • AML in second or subsequent morphologic remission (includes myeloid sarcoma).
    • CML in first chronic phase with detectable molecular or cytogenetic evidence of disease despite medical therapy; or CML with a history of accelerated or blast crisis, now in chronic phase; or unable to tolerate tyrosine kinase inhibitor therapy.
    • Juvenile myelomonocytic leukemia (JMML).
    • Myelodysplastic syndrome (MDS).
    • Therapy related (secondary) AML, ALL, or MDS.
    • Hodgkin lymphoma after failure of prior autologous HSCT or unsuitable for autologous HSCT.
    • Non-Hodgkin lymphoma (NHL) in second complete remission (CR2) or subsequent.
  • Has not received a prior allogeneic hematopoietic stem cell transplant.
  • Does not have a suitable HLA-matched sibling donor available for stem cell donation.
  • Does not have a suitable cord blood product or volunteer matched unrelated donor (MUD) available in the necessary time for stem cell donation.
  • Has a suitable HLA partially matched family member available for stem cell donation.
  • Cardiac shortening fraction greater than or equal to 25%.
  • Creatinine clearance or glomerular filtration rate (GFR) greater than or equal to 40 ml/min/1.73 m^2.
  • Forced vital capacity (FVC) greater than or equal to 40% of predicted value or a pulse oximetry value of greater than or equal to 92% on room air.
  • Direct bilirubin less than or equal to 3 mg/dl.
  • Age-dependent performance score of greater than or equal to 50.
  • Serum glutamic pyruvic transaminase (SGPT) less than 3 times the upper limit of normal for age.
  • Karnofsky or Lansky (age-dependent) performance score of greater than or equal to 50.
  • No known allergy to murine products or human anti-mouse antibody (HAMA) results within normal limits.
  • Not pregnant (confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment).
  • Not breast feeding.

Inclusion criteria (stem cell donor):

  • Partially HLA matched family member.
  • At least 18 years of age.
  • Human immunodeficiency virus (HIV) negative.
  • Not pregnant (confirmed by negative serum or urine pregnancy test within 7 days prior to enrollment).
  • Not breast feeding.

Inclusion criteria (transplant recipient - stem cell boost)

Has experienced one of the following disorders post-transplant:

  • graft failure
  • graft rejection
  • delayed hematopoietic and/or immune reconstitution.

Exclusion: NA

Sites / Locations

  • St. Jude Children's Research Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

High-Risk Hematologic Malignancies

Arm Description

Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF. Grafts from suitable haploidentical donors are processed using the CliniMACS system.

Outcomes

Primary Outcome Measures

Event-free Survival (EFS)
To determine if one year event-free survival can be improved in pediatric patients undergoing a haploidentical transplant by using a reduced intensity conditioning regimen and a targeted dose T cell depleted donor product. EFS is defined as time from transplantation to the occurrence of relapse or death due to any cause. Patients who are alive at the time of analysis will be censored. The estimated percentage of participants with EFS at one-year post-transplantation is reported using Kaplan-Meier analysis.

Secondary Outcome Measures

Overall Survival (OS)
Estimate the one-year overall survival (OS) for research participants who receive this study treatment. OS is defined as time from transplantation to death due to any cause. Patient who are alive at the time of analysis will be censored. The estimated percentage of participants with OS at one-year post-transplantation is reported using Kaplan-Meier analysis.
Disease-Free Survival (DFS)
Estimate the one-year disease-free survival (DFS) for research participants who receive this study treatment. DFS is defined as time from transplantation to the occurrence of relapse or death due to relapse. Patients who are alive at the time of analysis or die due to other causes will be censored at the time of their events. The estimated percentage of participants with DFS at one-year post-transplantation is reported using Kaplan-Meier analysis.
Incidence of Non-hematologic Regimen-related Toxicities
Estimate of the incidence of non-hematologic regimen-related toxicity and regimen-related toxicity in the first 100 days post-transplant. The percentage of participants are reported by maximum grade seen using binomial distribution. Participants were graded for toxicity using Common Terminology Criteria for Adverse Events version 3.0. In general, Grade 1 is mild, 2 is moderate toxicity but generally does not require treatment, 3 is severe enough to require treatment, 4 is life-threatening, and 5 means it was associated with death.
Incidence of Regimen-related Mortality
The incidence of regimen-related mortality in the first 100 days post-transplant is estimated based on binomial distribution.
To Estimate the Cumulative Incidence of Relapse for Research Participants Who Receive This Study Treatment.
The Cumulative Incidence of Relapse will be reported as the proportion of number of relapses since transplant to the total number of patients at risk at five years post-transplant.
To Estimate the Rate of Overall Grade III-IV Acute GVHD, and the Rate and Severity of Chronic GVHD in Research Participants.
The rate of Overall Grade III-IV Acute AVHD will be report as the proportion of patients who have Grade III-IV Acute GVHD to the total patients with transplant. The rate of Chronic GVHD will be report as the proportion of patients who have Chronic GVHD to the total patients with transplant. The Severity of Chronic GVHD will be reported using CTCAE grading system, as a number.

Full Information

First Posted
November 29, 2007
Last Updated
April 3, 2020
Sponsor
St. Jude Children's Research Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT00566696
Brief Title
Mismatched Family Member Donor Transplantation for Children and Young Adults With High Risk Hematological Malignancies
Official Title
A Reduced Intensity Conditioning Regimen With CD3-Depleted Hematopoietic Stem Cells to Improve Survival for Patients With Hematologic Malignancies Undergoing Haploidentical Stem Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
October 2019
Overall Recruitment Status
Completed
Study Start Date
December 14, 2007 (Actual)
Primary Completion Date
January 27, 2016 (Actual)
Study Completion Date
February 6, 2020 (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
Yes

5. Study Description

Brief Summary
Blood and marrow stem cell transplant has improved the outcome for patients with high-risk hematologic malignancies. However, most patients do not have an appropriate HLA (immune type) matched sibling donor available and/or are unable to identify an acceptable unrelated HLA matched donor through the registries in a timely manner. Another option is haploidentical transplant using a partially matched family member donor. Although haploidentical transplant has proven curative in many patients, this procedure has been hindered by significant complications, primarily regimen-related toxicity including GVHD and infection due to delayed immune reconstitution. These can, in part, be due to certain white blood cells in the graft called T cells. GVHD happens when the donor T cells recognize the body tissues of the patient (the host) are different and attack these cells. Although too many T cells increase the possibility of GVHD, too few may cause the recipient's immune system to reconstitute slowly or the graft to fail to grow, leaving the patient at high-risk for significant infection. For these reasons, a primary focus for researchers is to engineer the graft to provide a T cell dose that will reduce the risk for GVHD, yet provide a sufficient number of cells to facilitate immune reconstitution and graft integrity. Building on prior institutional trials, this study will provide patients with a haploidentical (HAPLO) graft engineered to specific T cell target values using the CliniMACS system. A reduced intensity, preparative regimen will be used in an effort to reduce regimen-related toxicity and mortality. The primary aim of the study is to help improve overall survival with haploidentical stem cell transplant in this high risk patient population by 1) limiting the complication of graft versus host disease (GVHD), 2) enhancing post-transplant immune reconstitution, and 3) reducing non-relapse mortality.
Detailed Description
This study will explore the following objectives: To assess if the event-free survival at one-year post-transplant for research participants with high-risk hematologic malignancies can be improved following HAPLO hematopoietic stem cell transplant (HSCT) using a graft depleted of CD3+ cells ex vivo and a reduced intensity-conditioning regimen. Secondary objectives: To estimate the one-year overall survival (OS) and disease-free survival (DFS) for research participants who receive this study treatment. To estimate the cumulative incidence of relapse for research participants who receive this study treatment. To estimate the rate of overall grade III-IV acute GVHD, and the rate and severity of chronic GVHD in research participants. To estimate the incidence of non-hematologic regimen-related toxicity and regimen-related mortality in the first 100 days post-transplant. Exploratory objectives: To explore the biologic significance of soluble interleukin-2 receptor and immunologic state [quantitative lymphocyte studies, V beta spectratyping, T-cell receptor excision circles (TREC) assay] to predict the development of acute and chronic GVHD in these research participants. To measure the pharmacokinetics of Campath-1H in pediatric HAPLO HSCT recipients NOTE: This protocol originally used muromonab (OKT3) in the conditioning regimen to prepare participants for haploidentical HCT. After muromonab became unavailable from the manufacturer in 2010, muromonab was replaced by alemtuzumab (Campath-1H) for use in subsequent participants.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Acute Lymphocytic (ALL), Leukemia, Myeloid, Acute(AML), Leukemia, Myeloid, Chronic(CML), Juvenile Myelomonocytic Leukemia (JMML), Hemoglobinuria, Paroxysmal Nocturnal (PNH), Hodgkin Lymphoma, Lymphoma, Non-Hodgkin (NHL), Myelodysplastic Syndrome (MDS)
Keywords
Haploidentical stem cell transplant, Allogeneic stem cell transplant, Mismatched family member stem cell donor transplant, Bone marrow transplant, High risk hematologic malignancies, T cell depletion methodology, Miltenyi Biotec CliniMACS stem cell selection device, Campath-1H intravenous

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
High-Risk Hematologic Malignancies
Arm Type
Experimental
Arm Description
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF. Grafts from suitable haploidentical donors are processed using the CliniMACS system.
Intervention Type
Device
Intervention Name(s)
CliniMACS
Intervention Description
Miltenyi Biotec CliniMACS stem cell selection device
Intervention Type
Procedure
Intervention Name(s)
Stem cell transplantation
Intervention Description
An infusion of HLA mismatched family member donor stem cells processed through the use of the investigational Miltenyi Biotec CliniMACS device.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Intervention Type
Drug
Intervention Name(s)
Thioplex®
Other Intervention Name(s)
Thiotepa, TESPA, TSPA
Intervention Description
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Intervention Type
Drug
Intervention Name(s)
L-phenylalanine mustard
Other Intervention Name(s)
Melphalan, Phenylalanine mustard, L-PAM, L-sarcolysin, Alkeran
Intervention Description
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil
Other Intervention Name(s)
MMF, CellCept®
Intervention Description
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Intervention Type
Drug
Intervention Name(s)
Rituxan™
Other Intervention Name(s)
Rituximab
Intervention Description
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Intervention Type
Drug
Intervention Name(s)
Alemtuzumab
Other Intervention Name(s)
Campath-1H, Campath®
Intervention Description
After January 2010, due to the unavailability of muromonab, transplant recipients received a conditioning regimen consisting of systemic chemotherapy and antibodies, including alemtuzumab.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Intervention Type
Drug
Intervention Name(s)
Anti-thymocyte globulin (Rabbit)
Other Intervention Name(s)
Thymoglobulin®, Rabbit ATG
Intervention Description
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Intervention Type
Drug
Intervention Name(s)
G-CSF
Other Intervention Name(s)
Filgrastim, Neupogen®
Intervention Description
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Intervention Type
Drug
Intervention Name(s)
Muromonab
Other Intervention Name(s)
OKT3, Muromonab-CD3
Intervention Description
Prior to January 2010, transplant participants received a conditioning regimen consisting of systemic chemotherapy and antibodies, including muromonab. Muromonab became unavailable from the manufacturer at that time and was replaced by alemtuzumab.
Primary Outcome Measure Information:
Title
Event-free Survival (EFS)
Description
To determine if one year event-free survival can be improved in pediatric patients undergoing a haploidentical transplant by using a reduced intensity conditioning regimen and a targeted dose T cell depleted donor product. EFS is defined as time from transplantation to the occurrence of relapse or death due to any cause. Patients who are alive at the time of analysis will be censored. The estimated percentage of participants with EFS at one-year post-transplantation is reported using Kaplan-Meier analysis.
Time Frame
one year post-transplant
Secondary Outcome Measure Information:
Title
Overall Survival (OS)
Description
Estimate the one-year overall survival (OS) for research participants who receive this study treatment. OS is defined as time from transplantation to death due to any cause. Patient who are alive at the time of analysis will be censored. The estimated percentage of participants with OS at one-year post-transplantation is reported using Kaplan-Meier analysis.
Time Frame
one year post-transplant
Title
Disease-Free Survival (DFS)
Description
Estimate the one-year disease-free survival (DFS) for research participants who receive this study treatment. DFS is defined as time from transplantation to the occurrence of relapse or death due to relapse. Patients who are alive at the time of analysis or die due to other causes will be censored at the time of their events. The estimated percentage of participants with DFS at one-year post-transplantation is reported using Kaplan-Meier analysis.
Time Frame
One year post-transplant
Title
Incidence of Non-hematologic Regimen-related Toxicities
Description
Estimate of the incidence of non-hematologic regimen-related toxicity and regimen-related toxicity in the first 100 days post-transplant. The percentage of participants are reported by maximum grade seen using binomial distribution. Participants were graded for toxicity using Common Terminology Criteria for Adverse Events version 3.0. In general, Grade 1 is mild, 2 is moderate toxicity but generally does not require treatment, 3 is severe enough to require treatment, 4 is life-threatening, and 5 means it was associated with death.
Time Frame
100 days post-transplant
Title
Incidence of Regimen-related Mortality
Description
The incidence of regimen-related mortality in the first 100 days post-transplant is estimated based on binomial distribution.
Time Frame
100 days post-transplant
Title
To Estimate the Cumulative Incidence of Relapse for Research Participants Who Receive This Study Treatment.
Description
The Cumulative Incidence of Relapse will be reported as the proportion of number of relapses since transplant to the total number of patients at risk at five years post-transplant.
Time Frame
five years post-transplant
Title
To Estimate the Rate of Overall Grade III-IV Acute GVHD, and the Rate and Severity of Chronic GVHD in Research Participants.
Description
The rate of Overall Grade III-IV Acute AVHD will be report as the proportion of patients who have Grade III-IV Acute GVHD to the total patients with transplant. The rate of Chronic GVHD will be report as the proportion of patients who have Chronic GVHD to the total patients with transplant. The Severity of Chronic GVHD will be reported using CTCAE grading system, as a number.
Time Frame
five years post-transplant

10. Eligibility

Sex
All
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:(transplant recipient) Patients less than or equal to 21 years of age; may be greater than 21 years old if a current St. Jude patient or previously treated St. Jude patient within 3 years of completion of prior treatment. Must have one of the following diagnosis: ALL high risk in second remission. Examples include relapse on therapy, first remission duration of less than or equal to 30 months, or relapse within 12 months of completing therapy. ALL in third or subsequent remission. ALL high risk in first remission. Examples include: induction failure, minimal residual disease greater than or equal to 1% marrow blasts by morphology after induction, persistent or recurrent cytogenetic or molecular evidence of disease during therapy requiring additional therapy after induction to achieve remission. High-risk AML in first remission. Examples include monosomy 7, M6, M7, t(6;9), FLT3-ITD, or patients who have greater than or equal to 25% blasts by morphology after induction or who do not achieve CR after 2 courses of therapy (includes myeloid sarcoma). Relapsed or persistent AML (less than or equal to 25% blasts in marrow by morphology). AML in second or subsequent morphologic remission (includes myeloid sarcoma). CML in first chronic phase with detectable molecular or cytogenetic evidence of disease despite medical therapy; or CML with a history of accelerated or blast crisis, now in chronic phase; or unable to tolerate tyrosine kinase inhibitor therapy. Juvenile myelomonocytic leukemia (JMML). Myelodysplastic syndrome (MDS). Therapy related (secondary) AML, ALL, or MDS. Hodgkin lymphoma after failure of prior autologous HSCT or unsuitable for autologous HSCT. Non-Hodgkin lymphoma (NHL) in second complete remission (CR2) or subsequent. Has not received a prior allogeneic hematopoietic stem cell transplant. Does not have a suitable HLA-matched sibling donor available for stem cell donation. Does not have a suitable cord blood product or volunteer matched unrelated donor (MUD) available in the necessary time for stem cell donation. Has a suitable HLA partially matched family member available for stem cell donation. Cardiac shortening fraction greater than or equal to 25%. Creatinine clearance or glomerular filtration rate (GFR) greater than or equal to 40 ml/min/1.73 m^2. Forced vital capacity (FVC) greater than or equal to 40% of predicted value or a pulse oximetry value of greater than or equal to 92% on room air. Direct bilirubin less than or equal to 3 mg/dl. Age-dependent performance score of greater than or equal to 50. Serum glutamic pyruvic transaminase (SGPT) less than 3 times the upper limit of normal for age. Karnofsky or Lansky (age-dependent) performance score of greater than or equal to 50. No known allergy to murine products or human anti-mouse antibody (HAMA) results within normal limits. Not pregnant (confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment). Not breast feeding. Inclusion criteria (stem cell donor): Partially HLA matched family member. At least 18 years of age. Human immunodeficiency virus (HIV) negative. Not pregnant (confirmed by negative serum or urine pregnancy test within 7 days prior to enrollment). Not breast feeding. Inclusion criteria (transplant recipient - stem cell boost) Has experienced one of the following disorders post-transplant: graft failure graft rejection delayed hematopoietic and/or immune reconstitution. Exclusion: NA
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://stjude.org
Description
St. Jude Children's Research Hospital
URL
http://www.stjude.org/protocols
Description
Clinical Trials Open at St. Jude

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Mismatched Family Member Donor Transplantation for Children and Young Adults With High Risk Hematological Malignancies

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