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

NCT ID: NCT00566696

Last Updated: 2020-04-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 73 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-12-14
• Study Completion Date: 2020-02-06

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:

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

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.

Conditions

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)

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

High-Risk Hematologic Malignancies

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.

Group Type: EXPERIMENTAL

CliniMACS

Intervention Type: DEVICE

Miltenyi Biotec CliniMACS stem cell selection device

Stem cell transplantation

Intervention Type: PROCEDURE

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

Fludarabine

Intervention Type: DRUG

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

Thioplex®

Intervention Type: DRUG

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

L-phenylalanine mustard

Intervention Type: DRUG

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

Mycophenolate mofetil

Intervention Type: DRUG

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

Rituxan™

Intervention Type: DRUG

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

Alemtuzumab

Intervention Type: DRUG

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

Cyclophosphamide

Intervention Type: DRUG

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

Anti-thymocyte globulin (Rabbit)

Intervention Type: DRUG

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

G-CSF

Intervention Type: DRUG

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

Muromonab

Intervention Type: 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.

Interventions

CliniMACS

Miltenyi Biotec CliniMACS stem cell selection device

Intervention Type: DEVICE

Stem cell transplantation

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

Intervention Type: PROCEDURE

Fludarabine

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

Intervention Type: DRUG

Thioplex®

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

Intervention Type: DRUG

L-phenylalanine mustard

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

Intervention Type: DRUG

Mycophenolate mofetil

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

Intervention Type: DRUG

Rituxan™

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

Intervention Type: DRUG

Alemtuzumab

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

Cyclophosphamide

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

Intervention Type: DRUG

Anti-thymocyte globulin (Rabbit)

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

Intervention Type: DRUG

G-CSF

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

Intervention Type: DRUG

Muromonab

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.

Intervention Type: DRUG

Other Intervention Names

Fludara; Thiotepa; TESPA; TSPA; Melphalan; Phenylalanine mustard; L-PAM; L-sarcolysin; Alkeran; MMF; CellCept®; Rituximab; Campath-1H; Campath®; Cytoxan; Thymoglobulin®; Rabbit ATG; Filgrastim; Neupogen®; OKT3; Muromonab-CD3

Eligibility Criteria

Inclusion Criteria

• 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.

• 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.

Has experienced one of the following disorders post-transplant:

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

Exclusion: NA

• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

St. Jude Children's Research Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Brandon Triplett, MD

Role: PRINCIPAL_INVESTIGATOR

St. Jude Children's Research Hospital

Locations

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://stjude.org

St. Jude Children's Research Hospital

http://www.stjude.org/protocols

Clinical Trials Open at St. Jude

Other Identifiers

NCI-2011-03670

Identifier Type: REGISTRY

Identifier Source: secondary_id

HIFLEX

Identifier Type: -

Identifier Source: org_study_id