Unrelated Umbilical Cord Blood Transplantation With Coinfusion of Mesenchymal Stem Cells

Study Overview
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Brief Summary
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A pilot study to assess the feasibility of unrelated umbilical cord blood transplantation with coinfusion of third-party mesenchymal stem cells after myeloablative or nonmyeloablative conditioning in patients with hematological malignancies. This is a multicenter single arm, phase I-II pilot study. The primary objective of this study is to determine the feasibility of Umbilical Cord Blood (UCB) Hematopoietic Stem Cell Transplantation (HSCT) with co-infusion of third party mesenchymal stem cells as assessed by the treatment-related mortality at d100 after transplant. Patient inclusion criteria: Age 15-60 yrs, Patients for whom allogeneic stem cell transplantation is the preferred treatment option, with the following hematological malignancies: acute myeloid leukemia, acute lymphoblastic leukemia, high risk myelodysplastic syndrome, advanced lymphoproliferative disorders, chronic myeloid leukemia (refractory or intolerant to second-line tyrosine kinase inhibitors), multiple myeloma, Informed consent given, Patient exclusion criteria, Previous allogeneic transplant, Progressive malignant disease, Significant organ damage as a contraindication to allotransplantation, Significant psychiatric or neurological disorder, Uncontrolled viral, fungal or bacterial infection, Pregnancy, HIV positive, Patients will receive either myeloablative or reduced intensity conditioning. One or 2 cord blood transplants will be transplanted, followed by infusion of a third-party mesenchymal stem cell transplant, Adverse event reporting Belgian Hematology Society (BHS) transplant committee will establish a protocol review committee which will organize a central monitoring of the study. Within the context of allogeneic Hematopoietic Stem Cell Transplantation (HSCTx) many severe events are likely to occur. Statistics and stopping rules: The trial will be stopped at any time that there is reasonable evidence that the true rate of day +100 nonrelapse mortality exceeds 0.40. It is the intention to include an initial 20 patients.

Detailed Description
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PROTOCOL SYNOPSIS Title of the study A pilot study to assess the feasibility of unrelated umbilical cord blood transplantation with coinfusion of third-party mesenchymal stem cells after myeloablative or nonmyeloablative conditioning in patients with hematological malignancies. Design of the study This is a multicenter single arm, phase I-II pilot study. Primary objective The primary objective of this study is to determine the feasibility of UCB HSCT with co-infusion of third party mesenchymal stem cells as assessed by the treatment-related mortality at d100 after transplant. Secondary objectives Chimerism at multiple time points Hematopoietic recovery (neutrophil and platelet engraftment) Immune recovery Incidence of acute and chronic graft-versus-host disease (GVHD) Infectious complications Disease free survival Relapse incidence Overall survival Graft criteria No peripheral blood or marrow donor available at the 9/10 compatibility level using high resolution typing techniques Adequate cord blood transplant available: a)Single cord blood Minimal 4/6 match (DR1-high, A-low, B-low) Minimal 2 (6/6), 2.5 (5/6) or 3 (4/6) x 10exp7 nucleated cells per kg in the graft b)Double cord blood At least 4/6 common antigens shared by recipient and the 2 cord blood transplants Minimal 3x 10exp7 nucleated cells per kg in the combined graft Patient inclusion criteria Age 15-60 yrs Allogeneic stem cell transplantation is the preferred treatment option: a)High risk acute myeloid leukemia (AML) in first complete remission (CR) Preceding myelodysplastic syndrome High risk karyotypes (e.g. monosomy 5 or 7, complex) Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3) alteration > 2 cycles to obtain CR Erythroblastic or megakaryocytic leukemia b)High risk acute lymphoblastic leukemia (ALL) in first CR High risk karyotypes (e.g. t[9;22], t[4;11], t[1;19], complex) Mixed lineage leukemia (MLL) rearrangements c)Acute leukemia in second or third remission d)High risk myelodysplastic syndrome: International Prognostic Scoring System (IPSS) Intermediate-2 or high risk e)Advanced lymphoproliferative disorders Diffuse large B-cel non-Hodgkin lymphoma (NHL) or mantle cell NHL or B-prolymphocytic leukemia Sensitive relapse after autologous HSCTx T-prolymphocytic leukemia Chronic lymphocytic leukemia Refractory to fludarabine Adverse karyotypes (del p17) f)Chronic myeloid leukemia Refractory or intolerant to second-line tyrosine kinase inhibitors g)Multiple myeloma Advanced disease (selected cases) Informed consent given Patient exclusion criteria Previous allogeneic transplant Progressive malignant disease Significant organ damage as a contraindication to allotransplantation Creatinine clearance < 60 ml/min Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) > 3x normal value and/or serum bilirubin >3 mg/dL Cardiac failure (LVEF < 50%) Clinical relevant pulmonary disease: Diffusing capacity of lung for carbon monoxide (DLCO) < 50% normal Significant psychiatric or neurological disorder Uncontrolled viral, fungal or bacterial infection Pregnancy HIV positive Study procedure Patients will receive either myeloablative or reduced intensity conditioning. One or 2 cord blood transplants will be transplanted, followed by infusion of a third-party mesenchymal stem cell transplant Adverse event reporting BHS transplant committee will establish a protocol review committee which will organize a central monitoring of the study. Within the context of allogeneic HSCTx many severe events are likely to occur. Statistics and stopping rules The trial will be stopped at any time that there is reasonable evidence that the true rate of day +100 nonrelapse mortality exceeds 0.40. It is the intention to include an initial 20 patients.

Official Title
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A Pilot Study to Assess the Feasibility of Unrelated Umbilical Cord Blood Transplantation With Coinfusion of Third-party Mesenchymal Stem Cells After Myeloablative or Nonmyeloablative Conditioning in Patients With Hematological Malignancies

Conditions
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Allogeneic Stem Cell Transplantation

Intervention / Treatment
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* Other: cord blood transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Allogeneic stem cell transplantation is the preferred treatment option: High risk acute myeloid leukemia (AML) in first complete remission (CR) Preceding myelodysplastic syndrome High risk karyotypes (e.g. monosomy 5 or 7, complex) FLT3 alteration > 2 cycles to obtain CR Erythroblastic or megakaryocytic leukemia High risk acute lymphoblastic leukemia (ALL) in first CR High risk karyotypes (e.g. t[9;22], t[4;11], t[1;19], complex) MLL rearrangements Acute leukemia in second or third remission High risk myelodysplastic syndrome: IPSS Intermediate-2 or high risk Advanced lymphoproliferative disorders Diffuse large B-cel non-Hodgkin lymphoma (NHL) or mantle cell NHL or B-prolymphocytic leukemia Sensitive relapse after autologous HSCTx T-prolymphocytic leukemia Chronic lymphocytic leukemia Refractory to fludarabine Adverse karyotypes (del p17) Chronic myeloid leukemia Refractory or intolerant to second-line tyrosine kinase inhibitors Multiple myeloma Advanced disease (selected cases) Informed consent given Exclusion Criteria: Previous allogeneic transplant Progressive malignant disease Significant organ damage as a contraindication to allotransplantation Creatinine clearance < 60 ml/min AST/ALT > 3x normal value and/or serum bilirubin > 3 mg/dL Cardiac failure (LVEF < 50%) Clinical relevant pulmonary disease: DLCO < 50% normal Significant psychiatric or neurological disorder Uncontrolled viral, fungal or bacterial infection Pregnancy HIV positive

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 60 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
Intervention Model: Single Group Assignment
Interventional Model Description: Patients will receive either myeloablative or reduced intensity conditioning. One or 2 cord blood transplants will be transplanted, followed by infusion of a third-party mesenchymal stem cell transplant
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cord blood transplant<br>Eligible patients receive cord blood transplantation with coinfusion of mesenchymal stem cells | Other: cord blood transplantation<br>* One or two cord blood transplants with co-infusion of third-party mesenchymal stem cells after pre-transplant preparative regimen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| treatment-related mortality | death related to treatment procedures | day 100 after transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematopoietic recovery | recovery of peripheral blood counts | One year after transplant |