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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by St. Jude Children's Research Hospital
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT00566696
First received: November 29, 2007
Last updated: May 22, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
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)
Device: CliniMACS
Procedure: Stem cell transplantation
Drug: Systemic chemotherapy and antibodies
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by St. Jude Children's Research Hospital:

Primary Outcome Measures:
  • 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. [ Time Frame: one year post-transplant ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To estimate the one-year overall survival (OS) and disease-free survival (DFS) for research participants who receive this study treatment. [ Time Frame: one year post-transplant ] [ Designated as safety issue: No ]
  • To estimate the cumulative incidence of relapse for research participants who receive this study treatment. [ Time Frame: three years post-transplant ] [ Designated as safety issue: No ]
  • To estimate the rate of overall grade III-IV acute GVHD, and the rate and severity of chronic GVHD in research participants. [ Time Frame: three years post-transplant ] [ Designated as safety issue: No ]
  • To estimate the incidence of non-hematologic regimen-related toxicity and regimen-related mortality in the first 100 days post-transplant. [ Time Frame: 100 days post-transplant ] [ Designated as safety issue: No ]

Estimated Enrollment: 102
Study Start Date: November 2007
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: High-Risk Hematologic Malignancies

Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies.

Grafts from suitable haploidentical donors are processed using the CliniMACS system.

Device: CliniMACS
Miltenyi Biotec CliniMACS stem cell selection device
Procedure: Stem cell transplantation
An infusion of HLA mismatched family member donor stem cells processed through the use of the investigational Miltenyi Biotec CliniMACS device.
Drug: Systemic chemotherapy and antibodies

Transplant recipients will receive a conditioning regimen consisting of the following:

Fludarabine

Thiotepa

Melphalan

Mycophenolate mofetil[MMF]

Rituximab

Hematopoietic stem cell [HSC infusion]

Granulocytic colony stimulating factor [G-CSF]

Other Names:
  • Fludara
  • Thioplex®
  • L-phenylalanine mustard
  • Alkeran
  • CellCept®
  • Rituxan™
  • Granulocytic Colony Stimulating Factor

Detailed Description:

This study will explore the following objectives:

  1. 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:

  1. To estimate the one-year overall survival (OS) and disease-free survival (DFS) for research participants who receive this study treatment.
  2. To estimate the cumulative incidence of relapse for research participants who receive this study treatment.
  3. To estimate the rate of overall grade III-IV acute GVHD, and the rate and severity of chronic GVHD in research participants.
  4. To estimate the incidence of non-hematologic regimen-related toxicity and regimen-related mortality in the first 100 days post-transplant.

Exploratory objectives:

  1. 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.
  2. To measure the pharmacokinetics of Campath-1H in pediatric HAPLO HSCT recipients
  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
    • Relapsed or persistent AML (less than or equal to 25% blasts in marrow by morphology).
    • AML in second or subsequent morphologic remission.
    • 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 in second or subsequent complete remission (CR) after prior autologous HSCT transplant or will be unable to have hematopoietic stem cells collected for autologous HSCT.
    • Non-Hodgkin lymphoma (NHL) in second or subsequent CR after prior autologous HSCT or unable to have stem cells collected for autologous HSCT.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00566696

Contacts
Contact: Brandon Triplett, MD 1-866-278-5833 info@stjude.org

Locations
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Brandon Triplett, MD    866-278-5833    info@stjude.org   
Principal Investigator: Brandon Triplett, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
Principal Investigator: Brandon Triplett, MD St. Jude Children's Research Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00566696     History of Changes
Other Study ID Numbers: HIFLEX
Study First Received: November 29, 2007
Last Updated: May 22, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by St. Jude Children's Research Hospital:
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

Additional relevant MeSH terms:
Neoplasms
Hemoglobinuria
Hemoglobinuria, Paroxysmal
Hodgkin Disease
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lymphoma
Lymphoma, Non-Hodgkin
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Hematologic Neoplasms
Proteinuria
Urination Disorders
Urologic Diseases
Urological Manifestations
Signs and Symptoms
Anemia, Hemolytic
Anemia
Hematologic Diseases
Bone Marrow Diseases
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders

ClinicalTrials.gov processed this record on July 22, 2014