Non-Myeloablative Conditioning for Unrelated Donor Umbilical Cord Blood Transplant

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill cancer cells. An umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving sirolimus and mycophenolate mofetil after the transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation followed by an umbilical cord blood transplant, sirolimus, and mycophenolate mofetil works in treating patients with hematologic cancer.

Detailed Description
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OBJECTIVES: Primary Determine the one- and two-year survival of patients with hematologic malignancies treated with a nonmyeloablative conditioning regimen comprising fludarabine, cyclophosphamide, and total-body irradiation followed by umbilical cord blood transplantation and post-transplant immunosuppression comprising sirolimus and mycophenolate mofetil. Secondary Determine the six-month nonrelapse mortality of patients treated with this regimen. Determine the presence of chimerism in patients treated with this regimen at days 21, 60, 100, 180, and 365. Determine the incidence of neutrophil engraftment by day 42 in patients treated with this regimen. Determine the incidence of platelet engraftment by six months in patients treated with this regimen. Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 in patients treated with this regimen. Determine the incidence of chronic GVHD at one year in patients treated with this regimen. Determine the probability of overall survival within one or two years in patients treated with this regimen. Determine the probability of progression-free survival within one or two years in patients treated with this regimen. Determine the incidence of relapse or disease progression within one or two years in patients treated with this regimen. OUTLINE: This is a nonrandomized study. Patients are stratified into five disease groups: 1. acute myeloid leukemia, myelodysplastic syndromes, chronic myelogenous leukemia [CML] in first chronic phase and second chronic phase [CP2] after myeloid blast crisis; 2. acute lymphoblastic leukemia, Burkitt's lymphoma, CML CP2 post lymphoid blast crisis, 3. large-cell B and T-cell lymphoma, mantle cell lymphoma; 4. chronic lymphocytic leukemia/small lymphocytic lymphoma, prolymphocytic leukemia, marginal zone B-cell lymphoma, follicular lymphoma; 5. Hodgkin's lymphoma and multiple myeloma. Nonmyeloablative conditioning: Patients receive fludarabine intravenously on days -6 to -2 and cyclophosphamide IV on day -6. Patients who did not undergo prior autologous transplant or who received ≤ 1 course of prior multiagent chemotherapy or no severely immunosuppressive therapy in the past 3 months also receive anti-thymocyte globulin IV on days -6 to -4. All patients also undergo total-body irradiation on day -1. Umbilical cord blood transplant: Patients undergo umbilical cord blood transplantation on day 0. Post-transplant immunosuppression: Sirolimus will be administered starting at day -3 with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2 weeks, weekly until day +60, and as clinically indicated until day +100 post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at day +100 and eliminated by day +180 post-transplantation. Patients also receive mycophenolate mofetil IV on days -3 to 5 and then orally on days 6-30. After completion of study treatment, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 320 patients will be accrued for this study.

Official Title
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Transplantation of Unrelated Donor Umbilical Cord Blood in Patients With Hematological Malignancies Using a Non-Myeloablative Preparative Regimen

Conditions
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Myeloproliferative Disorders, Leukemia, Lymphoma, Myelodysplastic Syndromes

Intervention / Treatment
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* Biological: anti-thymocyte globulin
* Drug: cyclophosphamide
* Drug: Fludarabine
* Drug: mycophenolate mofetil
* Procedure: umbilical cord blood transplantation
* Radiation: total body irradiation
* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age, Graft Cell Dose and Graft HLA Criteria Subjects must be <70 years old. Subjects ages ≥ 70 and ≤ 75 may be eligible if they have a Co-Morbidity Scoring (HCT-CI) score ≤ 2. The UCB graft is matched at 4-6 HLA-A, B, DRB1 antigens with the recipient. Patients co-enrolled in MT-2006-01 Phase I Study of Infusion of Umbilical Cord Blood Derived CD25+CD4+ T-Regulatory (Treg) Cells after Non-Myeloablative Cord\Blood Transplantation will receive grafts composed of 2 UCB units. Disease Criteria: Acute Leukemias: Acute myeloid leukemia: high risk complete remission 1 (CR1) (as evidenced by preceding myelodysplastic syndrome (MDS), high risk cytogenetics such as those associated with MDS or complex karyotype, > 2 cycles to obtain CR or erythroblastic and megakaryocytic); second or greater CR. Acute lymphoblastic leukemia/lymphoma: high risk CR1 as evidenced by high risk cytogenetics (e.g. t(9;22), t(1;19),t(4;11), other myeloid/lymphoid or mixed lineage leukemia [MLL] rearrangements, hypodiploidy or Ikaros family zinc finger 1 [IKZF1]), > 1 cycle to obtain CR or evidence of minimal residual disease (MRD). Patients in second or greater CR are also eligible. Burkitt's lymphoma in CR2 or subsequent CR Natural Killer cell malignancies Chronic myelogenous leukemia: all types except refractory blast crisis. Chronic phase patients must have failed or been intolerant to Gleevec Myelodysplastic syndrome: Large-cell lymphoma, Hodgkin lymphoma and multiple myeloma with chemotherapy sensitive disease that has failed or patients who are ineligible for an autologous transplant. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma, which have progressed within 12 months of achieving a partial or complete remission. Patients who had remissions lasting > 12 months, are eligible after at least two prior therapies. Patients with bulky disease should be considered for debulking chemotherapy before transplant. Patients with refractory disease are eligible, unless has bulky disease and an estimated tumor doubling time of less than one month. Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy if chemotherapy sensitive. Refractory leukemia or MDS. Bone marrow failure syndromes, except for Fanconi Anemia Myeloproliferative syndromes Patients who have undergone an autologous transplant >12 months prior to allogeneic transplantation Adequate Organ Function and Performance Status Exclusion Criteria: < 70 years with an available 5-6/6 HLA-A, B, DRB1 matched sibling donor Pregnancy or breastfeeding Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology Current active serious infection Unless in post-chemotherapy and radioimmunoconjugated antibody induced aplasia, when he/she would be eligible for Arm 3, patients with acute leukemia in morphologic relapse/ persistent disease defined as > 5% blasts in normocellular bone marrow OR any % blasts if blasts have unique morphologic markers (e.g. Auer rods) or associated cytogenetic markers that allows morphologic relapse to be distinguished are not eligible. Chronic myelogenous leukemia (CML) in refractory blast crisis Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressive on salvage therapy. Stable disease is acceptable to move forward provided it is non-bulky. Active central nervous system malignancy

Ages Eligible for Study
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Maximum Age: 75 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1-Previous Autologous Transplant<br>Arm 1 - hematologic malignancy patients who have received a previous autologous transplant or ≥ 2 cycle of multiagent chemotherapy within the last 3 months previous to umbilical cord blood transplant (UCBT). Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation without anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus. | Drug: cyclophosphamide<br>* Cyclophosphamide 50mg/kg x 1 to be administered IV over 2 hours with high volume fluid flush on day -6.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Fludarabine 40 mg/m2/day or 30 mg/m2/day intravenously (IV) as one hour infusion x 5 days, on day -6 to -2.<br>* Other names: Fludara;Drug: mycophenolate mofetil<br>* Mycophenolate mofetil (MMF) 3 gram/day for patients who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours.<br>* Other names: MMF;Procedure: umbilical cord blood transplantation<br>* One or 2 UCB units may be infused to achieve the required cell dose.<br>* Other names: UCBT;Radiation: total body irradiation<br>* Administered Day -1, 200 cGy<br>* Other names: TBI;Drug: Sirolimus<br>* Sirolimus will be administered starting at day -3 with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2 weeks, weekly until day +60, and as clinically indicated until day +100 post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at day +100 and eliminated by day +180 post-transplantation.<br>* Other names: rapamycin;|
| Active Comparator: Arm 2 - No Prior Autologous Transplant<br>Arm 2 - hematologic malignancy patients who have not been treated with prior autologous transplant or ≤ 1 cycle of chemotherapy in the 3 months previous to umbilical cord blood transplant (UCBT), and who should receive anti-thymocyte globulin as conditioning regimen. Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation with anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus. | Biological: anti-thymocyte globulin<br>* Equine ATG dose is 15 mg/kg intravenously (IV) every 12 hours for 6 doses on days -6, - 5, and -4.<br>* Other names: ATG;Drug: cyclophosphamide<br>* Cyclophosphamide 50mg/kg x 1 to be administered IV over 2 hours with high volume fluid flush on day -6.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Fludarabine 40 mg/m2/day or 30 mg/m2/day intravenously (IV) as one hour infusion x 5 days, on day -6 to -2.<br>* Other names: Fludara;Drug: mycophenolate mofetil<br>* Mycophenolate mofetil (MMF) 3 gram/day for patients who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours.<br>* Other names: MMF;Procedure: umbilical cord blood transplantation<br>* One or 2 UCB units may be infused to achieve the required cell dose.<br>* Other names: UCBT;Radiation: total body irradiation<br>* Administered Day -1, 200 cGy<br>* Other names: TBI;Drug: Sirolimus<br>* Sirolimus will be administered starting at day -3 with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2 weeks, weekly until day +60, and as clinically indicated until day +100 post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at day +100 and eliminated by day +180 post-transplantation.<br>* Other names: rapamycin;|
| Active Comparator: Arm 3 - Refractory Leukemia/Lymphoma<br>Arm 3 - patients with refractory leukemia or lymphoma who have been rendered aplastic either by induction chemotherapy or radioimmunoconjugated monoclonal antibody therapy. Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation with anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus. | Biological: anti-thymocyte globulin<br>* Equine ATG dose is 15 mg/kg intravenously (IV) every 12 hours for 6 doses on days -6, - 5, and -4.<br>* Other names: ATG;Drug: cyclophosphamide<br>* Cyclophosphamide 50mg/kg x 1 to be administered IV over 2 hours with high volume fluid flush on day -6.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Fludarabine 40 mg/m2/day or 30 mg/m2/day intravenously (IV) as one hour infusion x 5 days, on day -6 to -2.<br>* Other names: Fludara;Drug: mycophenolate mofetil<br>* Mycophenolate mofetil (MMF) 3 gram/day for patients who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours.<br>* Other names: MMF;Procedure: umbilical cord blood transplantation<br>* One or 2 UCB units may be infused to achieve the required cell dose.<br>* Other names: UCBT;Radiation: total body irradiation<br>* Administered Day -1, 200 cGy<br>* Other names: TBI;Drug: Sirolimus<br>* Sirolimus will be administered starting at day -3 with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2 weeks, weekly until day +60, and as clinically indicated until day +100 post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at day +100 and eliminated by day +180 post-transplantation.<br>* Other names: rapamycin;|
| Active Comparator: Arm 4: MT2006-01 coenrolling patients<br>Arm 4 - hematologic malignancy patients enrolled in MT2006-01. Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation with or without anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus. | Drug: cyclophosphamide<br>* Cyclophosphamide 50mg/kg x 1 to be administered IV over 2 hours with high volume fluid flush on day -6.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Fludarabine 40 mg/m2/day or 30 mg/m2/day intravenously (IV) as one hour infusion x 5 days, on day -6 to -2.<br>* Other names: Fludara;Drug: mycophenolate mofetil<br>* Mycophenolate mofetil (MMF) 3 gram/day for patients who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours.<br>* Other names: MMF;Procedure: umbilical cord blood transplantation<br>* One or 2 UCB units may be infused to achieve the required cell dose.<br>* Other names: UCBT;Radiation: total body irradiation<br>* Administered Day -1, 200 cGy<br>* Other names: TBI;Drug: Sirolimus<br>* Sirolimus will be administered starting at day -3 with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2 weeks, weekly until day +60, and as clinically indicated until day +100 post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at day +100 and eliminated by day +180 post-transplantation.<br>* Other names: rapamycin;|
| Active Comparator: Arm 5 - Previous Autologous Transplant<br>Arm 5 - hematologic malignancy patients who have received a previous autologous transplant or ≥ 2 cycle of multiagent chemotherapy within the last 3 months previous to umbilical cord blood transplant (UCBT). Conditioning Fludarabine dose of 30 mg/m2/day x 5, cyclophosphamide and total body irradiation without anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus. | Drug: cyclophosphamide<br>* Cyclophosphamide 50mg/kg x 1 to be administered IV over 2 hours with high volume fluid flush on day -6.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Fludarabine 40 mg/m2/day or 30 mg/m2/day intravenously (IV) as one hour infusion x 5 days, on day -6 to -2.<br>* Other names: Fludara;Drug: mycophenolate mofetil<br>* Mycophenolate mofetil (MMF) 3 gram/day for patients who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours.<br>* Other names: MMF;Procedure: umbilical cord blood transplantation<br>* One or 2 UCB units may be infused to achieve the required cell dose.<br>* Other names: UCBT;Radiation: total body irradiation<br>* Administered Day -1, 200 cGy<br>* Other names: TBI;Drug: Sirolimus<br>* Sirolimus will be administered starting at day -3 with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2 weeks, weekly until day +60, and as clinically indicated until day +100 post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at day +100 and eliminated by day +180 post-transplantation.<br>* Other names: rapamycin;|
| Active Comparator: Arm 6 - No prior autologous transplant<br>Arm 6 - hematologic malignancy patients who have not been treated with prior autologous transplant or ≤ 1 cycle of chemotherapy in the 3 months previous to umbilical cord blood transplant (UCBT), and who should receive anti-thymocyte globulin as conditioning regimen. Conditioning Fludarabine dose of 30 mg/m2/day x 5, cyclophosphamide and total body irradiation with anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus. | Biological: anti-thymocyte globulin<br>* Equine ATG dose is 15 mg/kg intravenously (IV) every 12 hours for 6 doses on days -6, - 5, and -4.<br>* Other names: ATG;Drug: cyclophosphamide<br>* Cyclophosphamide 50mg/kg x 1 to be administered IV over 2 hours with high volume fluid flush on day -6.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Fludarabine 40 mg/m2/day or 30 mg/m2/day intravenously (IV) as one hour infusion x 5 days, on day -6 to -2.<br>* Other names: Fludara;Drug: mycophenolate mofetil<br>* Mycophenolate mofetil (MMF) 3 gram/day for patients who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours.<br>* Other names: MMF;Procedure: umbilical cord blood transplantation<br>* One or 2 UCB units may be infused to achieve the required cell dose.<br>* Other names: UCBT;Radiation: total body irradiation<br>* Administered Day -1, 200 cGy<br>* Other names: TBI;Drug: Sirolimus<br>* Sirolimus will be administered starting at day -3 with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2 weeks, weekly until day +60, and as clinically indicated until day +100 post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at day +100 and eliminated by day +180 post-transplantation.<br>* Other names: rapamycin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Were Alive at 1 Year Post Transplant | Overall Survival - Number of patients alive at 1 year post transplant | 1 Year | 
| Number of Participants Who Were Alive at 2 Years Post Transplant | Overall Survival - Number of patients alive at 2 years post transplant | 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Were Dead at 6 Months After Study Completion | Incidence of Non-relapse mortality - Number of Patients Dead at 6 Months after study completion | Month 6 | 
| Percentage of Donor Chimerism at 21 Days | Chimerism studies will be performed on the blood and bone marrow (BM). BM chimerism days 21 and 100, at 6 months and 1 year to determine the relative contribution of donor and recipient hematopoiesis. | 21 days | 
| Percentage of Donor Chimerism at 100 Days | Chimerism studies will be performed on the blood and bone marrow (BM). BM chimerism days 21 and 100, at 6 months and 1 year to determine the relative contribution of donor and recipient hematopoiesis. | 100 days | 
| Percentage of Donor Chimerism at 180 Days | Chimerism studies will be performed on the blood and bone marrow (BM). BM chimerism days 21 and 100, at 6 months and 1 year to determine the relative contribution of donor and recipient hematopoiesis. | 180 Days | 
| Percentage of Donor Chimerism at 365 Days | Chimerism studies will be performed on the blood and bone marrow (BM). BM chimerism days 21 and 100, at 6 months and 1 year to determine the relative contribution of donor and recipient hematopoiesis. | 365 days | 
| Number of Participants With Neutrophil Engraftment | Time to 1st 3 consecutive days with absolute neutrophil count (ANC) > 5 x 10^8/L and percentage of patients with neutrophil recovery by day 42 (Cumulative incidence). | Day 42 | 
| Number of Participants With Platelet Engraftment | Time to platelets > 20,000 (first of 3 consecutive days) with no platelet transfusions for seven days and percentage of patients with platelet engraftment >50,000 by day 100. | Day 180 | 
| Number of Participants With Acute Graft-versus-host Disease (GVHD) | Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 post transplant. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria used for staging. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level. | Day 100 | 
| Number of Participants With Chronic Graft-Versus-Host Disease | Determine the incidence of chronic GVHD at 1 year after transplant. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level. | 1 Year | 
| Number of Participants Experiencing Progression-free Survival | Incidence of Progression-free survival - Number of patients who were alive and did not have disease progression. Patients with leukemia and lymphoma involving the bone marrow (BM) and multiple myeloma will have this done by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate. Patients with lymphoma and myeloma will have radiology studies such as plain X-rays or CT scans and/or other studies such as blood tumor markers to document presence or absence of disease as clinically indicated. | 1 Year | 
| Number of Participants Experiencing Progression-free Survival at 2 Years | Incidence of Progression-free survival - Number of patients who were alive and did not have disease progression | 2 Years | 
| Number of Participants Experiencing Relapse (Incidence of Relapse) | Patients with leukemia and lymphoma involving the BM and multiple myeloma will have this done by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate. Patients with lymphoma and myeloma will have radiology studies such as plain X-rays or CT scans and/or other studies such as blood tumor markers to document presence or absence of disease as clinically indicated. | Year 1 | 
| Number of Participants Experiencing Relapse (Incidence of Relapse) at 2 Years | Patients with leukemia and lymphoma involving the BM and multiple myeloma will have this done by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate. Patients with lymphoma and myeloma will have radiology studies such as plain X-rays or CT scans and/or other studies such as blood tumor markers to document presence or absence of disease as clinically indicated. | 2 years |