Myeloproliferative DisordersPhase 2NCT00305682
Non-Myeloablative Conditioning for Unrelated Donor Umbilical Cord Blood Transplant
A Phase 2 study testing anti-thymocyte globulin, cyclophosphamide and Fludarabine in people with Myeloproliferative Disorders and Leukemia, run by Masonic Cancer Center, University of Minnesota at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 75 years
- Conditions the study is for
- Myeloproliferative Disorders, Leukemia, Lymphoma
- What is being tested?
- anti-thymocyte globulin, cyclophosphamide and Fludarabine
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 295 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2005to 12 Dec 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 75 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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:
Show all 19Show fewer
- 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
Who cannot join
- < 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Masonic Cancer Center at University of Minnesota
Minneapolis, Minnesota, 55455
About this study
Official title: Transplantation of Unrelated Donor Umbilical Cord Blood in Patients With Hematological Malignancies Using a Non-Myeloablative Preparative Regimen
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.
Read the 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.
- Being tested
- anti-thymocyte globulin, cyclophosphamide, Fludarabine, mycophenolate mofetil, umbilical cord blood transplantation
- Medical subject headings
- Myeloproliferative Disorders, Leukemia, Lymphoma, Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
anti-thymocyte globulinBiological
Also called ATGAM, ATG
Equine ATG dose is 15 mg/kg intravenously (IV) every 12 hours for 6 doses on days -6, - 5, and -4.
cyclophosphamideDrug
Also called Cytoxan
Cyclophosphamide 50mg/kg x 1 to be administered IV over 2 hours with high volume fluid flush on day -6.
FludarabineDrug
Also called Fludara
Fludarabine 40 mg/m2/day or 30 mg/m2/day intravenously (IV) as one hour infusion x 5 days, on day -6 to -2.
Also called MMF
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.
umbilical cord blood transplantationProcedure or surgery
Also called UCBT
One or 2 UCB units may be infused to achieve the required cell dose.
total body irradiationRadiation
Also called TBI
Administered Day -1, 200 cGy
SirolimusDrug
Also called rapamycin
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.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1-Previous Autologous Transplant | Active comparator | 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. Receives: Drug: cyclophosphamide; Drug: Fludarabine; Drug: mycophenolate mofetil; Procedure: umbilical cord blood transplantation; Radiation: total body irradiation; Drug: Sirolimus |
| Arm 2 - No Prior Autologous Transplant | Active comparator | 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. Receives: Biological: anti-thymocyte globulin; Drug: cyclophosphamide; Drug: Fludarabine; Drug: mycophenolate mofetil; Procedure: umbilical cord blood transplantation; Radiation: total body irradiation; Drug: Sirolimus |
| Arm 3 - Refractory Leukemia/Lymphoma | Active comparator | 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. Receives: Biological: anti-thymocyte globulin; Drug: cyclophosphamide; Drug: Fludarabine; Drug: mycophenolate mofetil; Procedure: umbilical cord blood transplantation; Radiation: total body irradiation; Drug: Sirolimus |
| Arm 4: MT2006-01 coenrolling patients | Active comparator | 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. Receives: Drug: cyclophosphamide; Drug: Fludarabine; Drug: mycophenolate mofetil; Procedure: umbilical cord blood transplantation; Radiation: total body irradiation; Drug: Sirolimus |
| Arm 5 - Previous Autologous Transplant | Active comparator | 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. Receives: Drug: cyclophosphamide; Drug: Fludarabine; Drug: mycophenolate mofetil; Procedure: umbilical cord blood transplantation; Radiation: total body irradiation; Drug: Sirolimus |
| Arm 6 - No prior autologous transplant | Active comparator | 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. Receives: Biological: anti-thymocyte globulin; Drug: cyclophosphamide; Drug: Fludarabine; Drug: mycophenolate mofetil; Procedure: umbilical cord blood transplantation; Radiation: total body irradiation; Drug: Sirolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants Who Were Alive at 1 Year Post Transplant
Overall Survival - Number of patients alive at 1 year post transplant
Measured: 1 Year
Number of Participants Who Were Alive at 2 Years Post Transplant
Overall Survival - Number of patients alive at 2 years post transplant
Measured: 2 Years
Secondary outcomes (13)
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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Mar 2006 (estimated)
- Study startJun 2005
- Primary completion12 Dec 2019
- Study completion12 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Myeloproliferative DisordersStudies of the same condition, open and under way.
- More trials run by Masonic Cancer Center, University of MinnesotaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 295 participants (actual)
Sponsor and investigators
- Lead sponsor
- Masonic Cancer Center, University of Minnesota
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Claudio G. Brunstein, MD, PhD, Principal investigator, Masonic Cancer Center, University of Minnesota
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00305682
- Sponsor's protocol ID
- 2005LS036
- Other IDs
- UMN-MT-2005-02, UMN-0507M70121
- Status last verified
- Oct 2020
- First submitted
- 21 Mar 2006
- Last updated
- 19 Nov 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 19179301Brunstein 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.
PubMed 19167681Bachanova 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.
PubMed 22430088Bachanova 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.
PubMed 21403127MacMillan 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.
PubMed 18997171
Study at a glance
From the registry record, last updated by the sponsor on 19 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Transplantation of Unrelated Donor Umbilical Cord Blood in Patients With Hematological Malignancies Using a Non-Myeloablative Preparative Regimen
- ClinicalTrials.gov ID
- NCT00305682
- Acronym / sponsor ID
- 2005LS036
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 295 participants (actual)
- Lead sponsor
- Masonic Cancer Center, University of MinnesotaUniversity, hospital or other
- Study start
- Jun 2005 (actual)
- Primary completion
- 12 Dec 2019 (actual)
- Study completion
- 12 Dec 2019 (actual)
- First posted
- 22 Mar 2006 (estimated)
- Results
- Posted 2 Nov 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Arm 1-Previous Autologous Transplant | Active comparator | Drug: cyclophosphamide, Drug: Fludarabine, Drug: mycophenolate mofetil, Procedure: umbilical cord blood transplantation, Radiation: total body irradiation, Drug: SirolimusArm 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. |
| Arm 2 - No Prior Autologous Transplant | Active comparator | Biological: anti-thymocyte globulin, Drug: cyclophosphamide, Drug: Fludarabine, Drug: mycophenolate mofetil, Procedure: umbilical cord blood transplantation, Radiation: total body irradiation, Drug: SirolimusArm 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. |
| Arm 3 - Refractory Leukemia/Lymphoma | Active comparator | Biological: anti-thymocyte globulin, Drug: cyclophosphamide, Drug: Fludarabine, Drug: mycophenolate mofetil, Procedure: umbilical cord blood transplantation, Radiation: total body irradiation, Drug: SirolimusArm 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. |
| Arm 4: MT2006-01 coenrolling patients | Active comparator | Drug: cyclophosphamide, Drug: Fludarabine, Drug: mycophenolate mofetil, Procedure: umbilical cord blood transplantation, Radiation: total body irradiation, Drug: SirolimusArm 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. |
| Arm 5 - Previous Autologous Transplant | Active comparator | Drug: cyclophosphamide, Drug: Fludarabine, Drug: mycophenolate mofetil, Procedure: umbilical cord blood transplantation, Radiation: total body irradiation, Drug: SirolimusArm 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. |
| Arm 6 - No prior autologous transplant | Active comparator | Biological: anti-thymocyte globulin, Drug: cyclophosphamide, Drug: Fludarabine, Drug: mycophenolate mofetil, Procedure: umbilical cord blood transplantation, Radiation: total body irradiation, Drug: SirolimusArm 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. |
Who may qualify
- Ages
- Up to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (19 listed)
- 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.
- Acute Leukemias:
Key exclusion criteria (8 listed)
- < 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| anti-thymocyte globulinAlso: ATGAM, ATGEquine ATG dose is 15 mg/kg intravenously (IV) every 12 hours for 6 doses on days -6, - 5, and -4. | Biological | Arm 2 - No Prior Autologous Transplant, Arm 3 - Refractory Leukemia/Lymphoma, Arm 6 - No prior autologous transplant |
| cyclophosphamideAlso: CytoxanCyclophosphamide 50mg/kg x 1 to be administered IV over 2 hours with high volume fluid flush on day -6. | Drug | Arm 1-Previous Autologous Transplant, Arm 2 - No Prior Autologous Transplant, Arm 3 - Refractory Leukemia/Lymphoma, Arm 4: MT2006-01 coenrolling patients, Arm 5 - Previous Autologous Transplant, Arm 6 - No prior autologous transplant |
| FludarabineAlso: FludaraFludarabine 40 mg/m2/day or 30 mg/m2/day intravenously (IV) as one hour infusion x 5 days, on day -6 to -2. | Drug | Arm 1-Previous Autologous Transplant, Arm 2 - No Prior Autologous Transplant, Arm 3 - Refractory Leukemia/Lymphoma, Arm 4: MT2006-01 coenrolling patients, Arm 5 - Previous Autologous Transplant, Arm 6 - No prior autologous transplant |
| mycophenolate mofetilAlso: MMFMycophenolate 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. | Drug | Arm 1-Previous Autologous Transplant, Arm 2 - No Prior Autologous Transplant, Arm 3 - Refractory Leukemia/Lymphoma, Arm 4: MT2006-01 coenrolling patients, Arm 5 - Previous Autologous Transplant, Arm 6 - No prior autologous transplant |
| umbilical cord blood transplantationAlso: UCBTOne or 2 UCB units may be infused to achieve the required cell dose. | Procedure or surgery | Arm 1-Previous Autologous Transplant, Arm 2 - No Prior Autologous Transplant, Arm 3 - Refractory Leukemia/Lymphoma, Arm 4: MT2006-01 coenrolling patients, Arm 5 - Previous Autologous Transplant, Arm 6 - No prior autologous transplant |
| total body irradiationAlso: TBIAdministered Day -1, 200 cGy | Radiation | Arm 1-Previous Autologous Transplant, Arm 2 - No Prior Autologous Transplant, Arm 3 - Refractory Leukemia/Lymphoma, Arm 4: MT2006-01 coenrolling patients, Arm 5 - Previous Autologous Transplant, Arm 6 - No prior autologous transplant |
| SirolimusAlso: rapamycinSirolimus 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. | Drug | Arm 1-Previous Autologous Transplant, Arm 2 - No Prior Autologous Transplant, Arm 3 - Refractory Leukemia/Lymphoma, Arm 4: MT2006-01 coenrolling patients, Arm 5 - Previous Autologous Transplant, Arm 6 - No prior autologous transplant |
Primary outcome
Number of Participants Who Were Alive at 1 Year Post Transplant
Time frame: 1 Year
Overall Survival - Number of patients alive at 1 year post transplant
Number of Participants Who Were Alive at 2 Years Post Transplant
Time frame: 2 Years
Overall Survival - Number of patients alive at 2 years post transplant
13 secondary outcomes
Number of Participants Who Were Dead at 6 Months After Study Completion
Time frame: Month 6
Percentage of Donor Chimerism at 21 Days
Time frame: 21 days
Percentage of Donor Chimerism at 100 Days
Time frame: 100 days
Percentage of Donor Chimerism at 180 Days
Time frame: 180 Days
Percentage of Donor Chimerism at 365 Days
Time frame: 365 days
Number of Participants With Neutrophil Engraftment
Time frame: Day 42
Number of Participants With Platelet Engraftment
Time frame: Day 180
Number of Participants With Acute Graft-versus-host Disease (GVHD)
Time frame: Day 100
Number of Participants With Chronic Graft-Versus-Host Disease
Time frame: 1 Year
Number of Participants Experiencing Progression-free Survival
Time frame: 1 Year
Number of Participants Experiencing Progression-free Survival at 2 Years
Time frame: 2 Years
Number of Participants Experiencing Relapse (Incidence of Relapse)
Time frame: Year 1
Number of Participants Experiencing Relapse (Incidence of Relapse) at 2 Years
Time frame: 2 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Nov 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19179301Bachanova 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.
- Results publication: PubMed 19167681Brunstein 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.
- Derived from this study: PubMed 22430088Bachanova 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.
- Derived from this study: PubMed 21403127Bachanova 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.
- Derived from this study: PubMed 18997171MacMillan 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.
- https://pubmed.ncbi.nlm.nih.gov/19179301/Link provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Claudio G. Brunstein, MD, PhD principal investigator
Masonic Cancer Center, University of Minnesota
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing anti-thymocyte globulin, cyclophosphamide and Fludarabine in people with Myeloproliferative Disorders and Leukemia, run by Masonic Cancer Center, University of Minnesota at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Nov 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants Who Were Alive at 1 Year Post Transplant (time frame: 1 Year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00305682, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Nov 2020.