Randomized HaploCord Blood Transplantation vs. Double Umbilical Cord Blood Transplantation for Hematologic Malignancies

Study Overview
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Brief Summary
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The purpose of this study is compare the efficacy of haplo-cord transplant (investigational arm) with that of a more commonly used procedure in which only the cells contained in one or two umbilical cords are infused (standard arm). We hypothesize that reduced intensity conditioning and haplo-cord transplant results in fast engraftment of neutrophils and platelets, low incidences of acute and chronic graft versus host disease, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay and promising long term outcomes. We also hypothesize that umbilical cord blood selection can prioritize matching and better matched donors can be identified rapidly for most subjects.

Detailed Description
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This is a clinical trial for subjects with hematologic malignancies ( acute myelogenous leukemia, acute lymphocytic leukemia, Hodgkin's or Non-Hodgkin's lymphoma, or myelodysplastic syndrome) who are in need of a donor stem cell transplant, and for whom an umbilical cord blood transplant is thought to be the best option. For allogeneic transplant donors, we typically try to use related family members, such as brothers or sisters, or volunteer donors who are 'HLA matched', i.e. share similar proteins on their cells. This study is for subjects for whom such a matched sibling donor or a matched unrelated donor is not available. This study tests a new method of bone marrow transplantation called combined haplo-identical cord (haplo-cord) transplantation. In this procedure, cells from a related donor who shares half of the HLA proteins ( haplo-identical)are collected from the blood, as well as cells from an umbilical cord, and then both are transplanted. It is hoped that by using cells from a haplo-identical relative, subjects will have a faster recovery and require fewer transfusions. Over time the haplo-identical cells from the relative are replaced by the cells from the cord blood. The combined transplantation of haplo-identical stem cells and cord blood has previously been used in approximately 60 subjects with very encouraging results. The purpose of this study is to compare the efficacy of haplo-cord transplant ( investigational arm) with the more commonly used procedure in which only the cells contained in one or two umbilical cords are infused (standard arm). Subjects will be randomly assigned into either the haplo-cord group or the umbilical cord group. If randomized to the haplo-cord group, a family member will undergo a stem cell collection. In both arms, subjects will receive a conditioning regimen prior to transplantation. The conditioning regimen consists of chemotherapy, which is meant to destroy the cancer cells and suppress the immune system to allow the transplanted cells to grow. Subjects will remain in the hospital until the stem cells are fully recovered, which is usually 4 to 6 weeks after the transplant. Subjects will have bone marrow aspiration and biopsy at 3 weeks, 4 weeks, 2 months, 6 months and 1 year after the transplant and then yearly thereafter. Participation in the study will continue for up to 5 years after transplantation.

Official Title
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A Randomized Study of Combined Haplo-identical Umbilical Cord Blood Transplantation vs. Double Umbilical Cord Blood Transplantation in Patients With Hematologic Malignancies

Conditions
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Acute Myelogenous Leukemia, Myelodysplastic Syndrome, Acute Lymphocytic Leukemia, Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Device: CliniMACS® CD34 Reagent System
* Drug: Fludarabine
* Drug: Melphalan
* Drug: Rabbit ATG
* Procedure: Double Umbilical Cord Blood Transplantation
* Procedure: Haplo-Identical Cord Transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have a histologically or cytologically confirmed diagnosis of: Acute Myelogenous Leukemia Myelodysplastic Syndrome Acute Lymphocytic Leukemia Lymphoma (Hodgkin's Lymphoma or Non-Hodgkin's Lymphoma) Must be > 18 years of age Subject is likely to benefit from allogeneic transplant in the opinion of the transplant physician An human leukocyte antigen (HLA)-identical related or unrelated donor cannot be identified within an appropriate time frame Karnofsky Performance Status (KPS) of > 80 Subject has acceptable organ and marrow function as defined below: Serum bilirubin < 2.0mg/dL ALT(SGPT) 3 X upper limit of normal Creatinine Clearance > 50 mL/min as estimated by the modified MDRD equation.18 Ability to understand and the willingness to sign a written informed consent document. A preliminary search has identified both: Appropriate umbilical cords for a single, or if necessary a double umbilical cord blood (UCB) transplant AND An appropriate single UCB as well as an appropriate haplo donor for haplo-cord transplant Exclusion Criteria: Myeloproliferative disorders, hemoglobinopathies, severe aplastic anemia or any diagnosis not listed under 3.1.1 Life expectancy is severely limited by concomitant illness or uncontrolled infection Subjects with severely decreased Left Ventricular Ejection Fraction (LVEF) or impaired pulmonary function tests (PFTs) Subject has evidence of chronic active hepatitis or cirrhosis Subject is HIV-positive Subject is pregnant or lactating. -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Haplo-Cord SCT<br>The UCB unit must supply a minimum of 1.0 x107/kg pre-cryopreserved nucleated cell dose. The unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the allele level) loci. All typing will be done using molecular typing. Though molecular level typing will be available, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1 | Device: CliniMACS® CD34 Reagent System<br>* If a subject is randomized to the haplo-cord transplant group, their family member will undergo a stem cell collection. The stem cells from the haplo-identical donor will be purified by a procedure called CD34 selection before they are given to the subject. A special device called the CliniMACS® CD34 Reagent System, which is not FDA approved, will be used for this purpose. The manufacturer of the device, Miltenyi Biotec, is providing the researchers access to the device for use in this research study. Because the stem cells from the haplo-identical donor are treated using the CliniMACS CD34 selection device, they cells are considered investigational.<br>* Other names: Miltenyi CliniMACS® device;Drug: Fludarabine<br>* Fludarabine: 30 mg/m2 /day intravenously x 5 days total dose 150 mg/m2. Fludarabine will be dosed according to actual body weight<br>Drug: Melphalan<br>* Melphalan: 70mg/m2/day intravenously x 2 days. Melphalan will be dosed according to actual body weight. Cryotherapy with ice chips will be administered to prevent mucositis.<br>Drug: Rabbit ATG<br>* Rabbit ATG (rATG): 1.5 mg/kg/day intravenously x 4 days, total 6 mg/kg. ATG will be dosed according to actual body weight. The first dose will be infused over at least six hours, and subsequent doses over at least 4 hours. Pre-medications include acetaminophen 650 mg by mouth, diphenhydramine 25-50 mg by mouth or intravenously, and methylprednisolone 2 mg/kg (1 mg/ kg at the initiation and 1 mg/kg half-way through anti-thymocyte globulin administration).<br>* Other names: rATG;Procedure: Haplo-Identical Cord Transplantation<br>* If randomized to the haplo-cord group, a family member will undergo a stem cell collection. In both arms, subjects will receive a conditioning regimen prior to transplantation. The conditioning regimen utilized in this study incorporates fludarabine-Melphalan and antithymocyte globulin (ATG). This regimen has the advantage of being nearly identical to the regimen utilized for our haplo-cord regimen is based on the experience of the Dana-Farber/Mass-General regimen.<br>* Other names: Haplo-cord transplant;|
| Active Comparator: UCB SCT<br>For the standard arm, UCB units will be selected using the Minnesota strategy and the strategy followed in a recent CTN study.17;19Each unit must supply a minimum of 1.5 x107/kg pre-cryopreserved nucleated cell dose. Subjects must have two partially HLA-matched UCB units. Each unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the allele level) loci. All typing will be done using molecular typing. Though molecular level typing will be available, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1 | Drug: Fludarabine<br>* Fludarabine: 30 mg/m2 /day intravenously x 5 days total dose 150 mg/m2. Fludarabine will be dosed according to actual body weight<br>Drug: Melphalan<br>* Melphalan: 70mg/m2/day intravenously x 2 days. Melphalan will be dosed according to actual body weight. Cryotherapy with ice chips will be administered to prevent mucositis.<br>Drug: Rabbit ATG<br>* Rabbit ATG (rATG): 1.5 mg/kg/day intravenously x 4 days, total 6 mg/kg. ATG will be dosed according to actual body weight. The first dose will be infused over at least six hours, and subsequent doses over at least 4 hours. Pre-medications include acetaminophen 650 mg by mouth, diphenhydramine 25-50 mg by mouth or intravenously, and methylprednisolone 2 mg/kg (1 mg/ kg at the initiation and 1 mg/kg half-way through anti-thymocyte globulin administration).<br>* Other names: rATG;Procedure: Double Umbilical Cord Blood Transplantation<br>* All subjects will receive an UCB dose of > 3 x107/kg nucleated blood cells. It is expected that this will require co-infusion of two UCB in the large majority of cases. If two UCB are required, they will be at least 4/5 matched to the recipient.<br>* Other names: UCB SCT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Neutrophil Engraftment After Combined Haplo-identical Cord With That of Umbilical Cord Blood Transplantation. | No patients completed this study and are therefore inevaluable. Subject data not evaluable for the outcome measure time frame. Subject data only evaluable up to month 3. | estimation of 24 months to determine engraftment rates for all subjects | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet Recovery After Transplant Regimens | No patients completed this study and are therefore inevaluable | estimation of 24 months to determine platelet recovery for all subjects | 
| Transfusion Requirements After Haplo-identical Umbilical Cord Blood Transplant Versus Double Umbilical Cord Blood Transplant |  | estimation of 24 months to determine transfusion requirements of all subjects | 
| Transplant-related Mortality (TRM), Relapse Rate, Survival and Progression Free Survival |  | estimation of 24 months to obtain survival info between subjects | 
| Incidence of Acute and Chronic GVHD |  | estimation of 24 months to obtain GVHD data on all subjects | 
| Severity of Opportunistic Infections |  | estimation of 24 months to obtain infection data on all subjects | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Lymphoma