Clinical trial NCT00305682: Non-Myeloablative Conditioning for Unrelated Donor Umbilical Cord Blood Transplant
Official title: Transplantation of Unrelated Donor Umbilical Cord Blood in Patients With Hematological Malignancies Using a Non-Myeloablative Preparative Regimen
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myeloproliferative Disorders
Leukemia
Lymphoma
Myelodysplastic Syndromes
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2006-03-22
Enrollment: 295
Sex: ALL
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants Who Were Alive at 1 Year Post Transplant
timeFrame: 1 Year
measure: Number of Participants Who Were Alive at 2 Years Post Transplant
timeFrame: 2 Years
Secondary outcomes:
measure: Number of Participants Who Were Dead at 6 Months After Study Completion
timeFrame: Month 6
measure: Percentage of Donor Chimerism at 21 Days
timeFrame: 21 days
measure: Percentage of Donor Chimerism at 100 Days
timeFrame: 100 days
measure: Percentage of Donor Chimerism at 180 Days
timeFrame: 180 Days
measure: Percentage of Donor Chimerism at 365 Days
timeFrame: 365 days
measure: Number of Participants With Neutrophil Engraftment
timeFrame: Day 42
measure: Number of Participants With Platelet Engraftment
timeFrame: Day 180
measure: Number of Participants With Acute Graft-versus-host Disease (GVHD)
timeFrame: Day 100
measure: Number of Participants With Chronic Graft-Versus-Host Disease
timeFrame: 1 Year
measure: Number of Participants Experiencing Progression-free Survival
timeFrame: 1 Year
measure: Number of Participants Experiencing Progression-free Survival at 2 Years
timeFrame: 2 Years
measure: Number of Participants Experiencing Relapse (Incidence of Relapse)
timeFrame: Year 1
measure: Number of Participants Experiencing Relapse (Incidence of Relapse) at 2 Years
timeFrame: 2 years
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center at University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Claudio G. Brunstein, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bachanova V, Verneris MR, DeFor T, Brunstein CG, Weisdorf DJ. Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation. Blood. 2009 Mar 26;113(13):2902-5. doi: 10.1182/blood-2008-10-184093. Epub 2009 Jan 28.
citation: Brunstein CG, Cantero S, Cao Q, Majhail N, McClune B, Burns LJ, Tomblyn M, Miller JS, Blazar BR, McGlave PB, Weisdorf DJ, Wagner JE. Promising progression-free survival for patients low and intermediate grade lymphoid malignancies after nonmyeloablative umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2009 Feb;15(2):214-22. doi: 10.1016/j.bbmt.2008.11.013.
citation: Bachanova V, Burke MJ, Yohe S, Cao Q, Sandhu K, Singleton TP, Brunstein CG, Wagner JE, Verneris MR, Weisdorf DJ. Unrelated cord blood transplantation in adult and pediatric acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival. Biol Blood Marrow Transplant. 2012 Jun;18(6):963-8. doi: 10.1016/j.bbmt.2012.02.012. Epub 2012 Mar 16.
citation: Bachanova V, Sandhu K, Yohe S, Cao Q, Burke MJ, Verneris MR, Weisdorf D. Allogeneic hematopoietic stem cell transplantation overcomes the adverse prognostic impact of CD20 expression in acute lymphoblastic leukemia. Blood. 2011 May 12;117(19):5261-3. doi: 10.1182/blood-2011-01-329573. Epub 2011 Mar 14.
citation: MacMillan ML, Weisdorf DJ, Brunstein CG, Cao Q, DeFor TE, Verneris MR, Blazar BR, Wagner JE. Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors. Blood. 2009 Mar 12;113(11):2410-5. doi: 10.1182/blood-2008-07-163238. Epub 2008 Nov 7.