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Completed

NCT Number: NCT00566696

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

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.

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Key information

Conditions

Leukemia, Acute Lymphocytic (ALL) Anemia Anemia, Hemolytic Bone Marrow Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Hematologic Diseases Hemic and Lymphatic Diseases Hemoglobinuria Hemoglobinuria, Paroxysmal Hemoglobinuria, Paroxysmal Nocturnal (PNH) Hodgkin Disease Hodgkin Lymphoma Immune System Diseases Immunoproliferative Disorders Juvenile Myelomonocytic Leukemia (JMML) Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Leukemia, Myeloid, Acute(AML) Leukemia, Myeloid, Chronic(CML) Leukemia, Myelomonocytic, Juvenile Lymphatic Diseases Lymphoma Lymphoma, Non-Hodgkin Lymphoma, Non-Hodgkin (NHL) Lymphoproliferative Disorders Male Urogenital Diseases Myelodysplastic Syndrome (MDS) Myelodysplastic Syndromes Myelodysplastic-Myeloproliferative Diseases Neoplasms Neoplasms by Histologic Type Pathological Conditions, Signs and Symptoms Proteinuria Signs and Symptoms Urination Disorders Urogenital Diseases Urologic Diseases Urological Manifestations

Age range

Up to 21 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

CliniMACS

Device

Miltenyi Biotec CliniMACS stem cell selection device

stem cell transplantation

Procedure

An infusion of HLA mismatched family member donor stem cells processed through the use of the investigational Miltenyi Biotec CliniMACS device.

Fludarabine

Drug

Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.

Other names: Fludara

Thioplex®

Drug

Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.

Other names: Thiotepa, TESPA, TSPA

L-phenylalanine mustard

Drug

Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.

Other names: Melphalan, Phenylalanine mustard, L-PAM, L-sarcolysin, Alkeran

Mycophenolate mofetil

Drug

Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.

Other names: MMF, CellCept®

Rituxan™

Drug

Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.

Other names: Rituximab

Alemtuzumab

Drug

After January 2010, due to the unavailability of muromonab, transplant recipients received a conditioning regimen consisting of systemic chemotherapy and antibodies, including alemtuzumab.

Other names: Campath-1H, Campath®

Cyclophosphamide

Drug

Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.

Other names: Cytoxan

Anti-thymocyte globulin (rabbit)

Drug

Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.

Other names: Thymoglobulin®, Rabbit ATG

G-CSF

Drug

Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.

Other names: Filgrastim, Neupogen®

Muromonab

Drug

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.

Other names: OKT3, Muromonab-CD3

Primary outcomes

  1. Event-free Survival (EFS)

    Time frame: one year post-transplant

    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 outcomes

  1. Overall Survival (OS)

    Time frame: one year post-transplant

    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.

  2. Disease-Free Survival (DFS)

    Time frame: One year post-transplant

    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.

  3. Incidence of Non-hematologic Regimen-related Toxicities

    Time frame: 100 days post-transplant

    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.

  4. Incidence of Regimen-related Mortality

    Time frame: 100 days post-transplant

    The incidence of regimen-related mortality in the first 100 days post-transplant is estimated based on binomial distribution.

  5. To Estimate the Cumulative Incidence of Relapse for Research Participants Who Receive This Study Treatment.

    Time frame: five years post-transplant

    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.

  6. To Estimate the Rate of Overall Grade III-IV Acute GVHD, and the Rate and Severity of Chronic GVHD in Research Participants.

    Time frame: five years post-transplant

    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.

Sponsors and collaborators

Lead sponsor

St. Jude Children's Research Hospital

Other

Registry information

Official study 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

Important dates

Study start
2007
Primary completion
2016
Study completion
2020
First posted
Dec 3, 2007
Registry last updated
Apr 14, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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