Donor Umbilical Cord Blood Transplant After Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation in Treating Patients With High-Risk Hematologic Cancer

This study has been terminated.
(Lack of efficacy after interim analysis)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT00963872
First received: August 21, 2009
Last updated: March 15, 2013
Last verified: March 2013
  Purpose

RATIONALE: Giving low doses of chemotherapy and total-body irradiation before a donor umbilical cord blood transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect).

PURPOSE: This phase I trial is studying the safety of donor umbilical cord blood transplant after fludarabine phosphate, cyclophosphamide, and total-body irradiation in treating patients with high-risk hematologic cancer (now closed).

The Phase II part of this trial is studying whether priming one of two UCB units with C3a facilitates engraftment of the treated unit.


Condition Intervention Phase
Leukemia
Lymphoma
Multiple Myeloma
Myelodysplastic Syndromes
Drug: cyclophosphamide
Drug: fludarabine phosphate
Radiation: Total body irradiation
Biological: Umbilical cord blood unit with C3a fragment
Biological: Unmanipulated UCB Unit
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: MT2008-15: Transplantation of Unrelated Donor Umbilical Cord Blood in Patients With Hematological Malignancies Using a Nonmyeloablative Preparative Regimen and Priming With Complement 3a Fragment (C3a)

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Proportion of patients with the complement 3a (C3a) unit predominating [ Time Frame: Day 180 ] [ Designated as safety issue: No ]
    Efficacy of the pre-incubation of one of two umbilical cord blood (UCB) units with C3a as part of a unrelated donor double UCB nonmyeloablative transplantation in patients with high-risk hematological malignancies.


Secondary Outcome Measures:
  • Neutrophil Engraftment [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Achieving 500 neutrophils/uL by day 42.

  • Blood Chimerism [ Time Frame: Days 7, 14, 21, 28, 60 and 100 ] [ Designated as safety issue: No ]
    Proportion of donor DNA present in the peripheral blood

  • Incidence of grades II-IV and III-IV graft-vs-host disease [ Time Frame: Day 0 through Day 100 ] [ Designated as safety issue: Yes ]
    Development of graft-versus-host disease

  • Non-Relapse Mortality [ Time Frame: Day 180 and 360 ] [ Designated as safety issue: No ]
    Deaths not due to relapse.

  • Overall survival [ Time Frame: Day 360 and 720 ] [ Designated as safety issue: No ]
    Survival (alive) from transplantation to last follow-up.

  • Bone Marrow Chimerism [ Time Frame: Day 21, 100, 180, 360 and 720 ] [ Designated as safety issue: No ]
    Proportion of donor DNA in the bone marrow.

  • Chronic Graft-Versus-Host Disease [ Time Frame: Day 360 ] [ Designated as safety issue: No ]
    Patients who developed chronic graft-versus-host disease.

  • Relapse of Disease [ Time Frame: Day 360 and 720 ] [ Designated as safety issue: No ]
    Patients who developed disease relapse after transplantation.

  • Disease Progression [ Time Frame: Day 360 and 720 ] [ Designated as safety issue: No ]
    Patients who developed disease progression after transplantation.

  • Platelet Recovery [ Time Frame: Day 180 ] [ Designated as safety issue: No ]
    Proportion of patients with >50,000 or >20,000 platelets/uL by day 180


Enrollment: 34
Study Start Date: March 2010
Estimated Study Completion Date: August 2014
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Complement Fragment 3A - Small Cell Dose
Patients who received complement fragment 3a (C3a) priming of the UCB unit with the smaller cell dose following preparation regimen and radiation.
Drug: cyclophosphamide
50 mg/kg intravenously (IV) over 2 hours on Day -6.
Other Name: Cytoxan
Drug: fludarabine phosphate
40 mg/m^2 over 1 hour on Days -6 through -2.
Other Name: Fludara
Radiation: Total body irradiation
200 cGy on Day -1
Biological: Umbilical cord blood unit with C3a fragment
On Day 0, the C3a primed UCB unit will be infused intravenously SECOND, within 30 minutes of the completion of the infusion of the unmanipulated UCB unit, through a central line without in-line filtration in a manner identical to the unmanipulated UCB unit.
Biological: Unmanipulated UCB Unit
On Day 0, the unmanipulated UCB unit will be infused FIRST through a central line without in-line filtration per institutional guidelines.
Experimental: Complement Fragment A - Larger Cell Dose
Patients who received complement fragment 3a (C3a) priming of the UCB unit with the larger cell dose.
Drug: cyclophosphamide
50 mg/kg intravenously (IV) over 2 hours on Day -6.
Other Name: Cytoxan
Drug: fludarabine phosphate
40 mg/m^2 over 1 hour on Days -6 through -2.
Other Name: Fludara
Radiation: Total body irradiation
200 cGy on Day -1
Biological: Umbilical cord blood unit with C3a fragment
On Day 0, the C3a primed UCB unit will be infused intravenously SECOND, within 30 minutes of the completion of the infusion of the unmanipulated UCB unit, through a central line without in-line filtration in a manner identical to the unmanipulated UCB unit.
Biological: Unmanipulated UCB Unit
On Day 0, the unmanipulated UCB unit will be infused FIRST through a central line without in-line filtration per institutional guidelines.

Detailed Description:

OUTLINE:

  • Nonmyeloablative preparative regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on day -6. Patients then undergo total-body irradiation on day -1. Some patients also receive anti-thymocyte globulin IV every 12 hours on days -6, -5, and -4.
  • Umbilical cord blood (UCB) transplantation: Patients undergo unmanipulated UCB transplantation followed by complement 3a fragment primed UCB transplantation on day 0.

Treatment for graft-vs-host disease prophylaxis is also given.

After completion of study therapy, patients are followed up periodically for up to 2 years.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Disease Criteria

    • Acute Leukemias: Must be in remission by morphology (<5% blasts). Note cytogenetic relapse or persistent disease without morphologic relapse is acceptable. Also a small percentage of blasts that is equivocal between marrow regeneration vs. early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse. (See exclusion criteria for more detailed definition)
    • Acute myeloid leukemia: high risk CR1 (as evidenced by preceding myelodysplastic syndrome (MDS), high risk cytogenetics such as those associated with MDS or complex karyotype, > 2 cycles to obtain complete remission (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 MLL rearrangements) or > 1 cycle to obtain CR; second or greater CR.
    • Burkitt's lymphoma in CR2 or subsequent CR
    • Natural Killer cell malignancies
    • Myeloproliferative syndromes/diseases: Chronic myelogenous leukemia (CML) in chronic or accelerated phase but patients must have failed or been intolerant to Imatinib mesylate. EXCLUDED: CML in refractory blast crisis, myelofibrosis, polycythemia vera, and essential thrombocytosis.
    • Myelodysplastic Syndrome: any subtype including refractory anemia (RA) if severe pancytopenia, high risk complex cytogenetics or International Prognostic Scoring System (IPSS) ≥ intermediate-2 (Int-2). Blasts must be less than 5%. If 5% or more requires therapy pre-transplant to reduce blast count to ≤5%. Patients who receive single agent 5-azacytidine, decitabine or immunomodulating drugs are eligible.
    • Large-cell lymphoma, Hodgkin's lymphoma and multiple myeloma: patients with chemotherapy sensitive disease that has failed or who are ineligible for an autologous transplant. Patients are eligible for umbilical cord blood (UCB) transplantation if there is no evidence of progressive disease by imaging modalities and/or biopsy. Persistent PET activity, though possibly related to lymphoma, IS NOT an exclusion criterion in the absence of computated tomography (CT) changes in size indicating progression. Large-cell and Hodgkin's lymphoma that is progressive on salvage therapy is NOT eligible. Patients with stable disease are eligible for transplantation if the largest residual nodal mass is < 5 cm (approximately). For patients who have responded to preceding therapy, the largest residual mass must represent a 50% reduction and be < 7.5 cm (approximately).
    • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma which have progressed 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. Patients with stable disease are eligible for transplantation if the largest residual nodal mass is < 5 cm (approximately). For patients who have responded to preceding therapy, the largest residual mass must represent a 50% reduction and be < 7.5 cm (approximately).
    • Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy if chemotherapy sensitive. Mantle-cell lymphoma that is progressive on salvage therapy is NOT eligible. Patients with stable disease are eligible for transplantation if the largest residual nodal mass is < 5 cm (approximately). For patients who have responded to preceding therapy, the largest residual mass must represent a 50% reduction and be < 7.5 cm (approximately).
  • Umbilical Cord Blood Graft Selection - Two UCB units will be compose the graft, and each unit must be a 4-6 HLA-A, B, DRB1 antigen match to each other, as well as a 4-6 antigen match to the recipient. The combined cryopreserved nucleated cell dose of the 2 units must be ≥ 3 X 10^7/kg with each unit having a minimum cell dose of 1.5 X 10^7/kg. UCB units will be selected according to a common umbilical cord blood graft selection algorithm
  • Performance Status - adequate performance status defined as Karnofsky score ≥ 60
  • Age 18 to 70 years of age; patients ≥ 70 but ≤ 75 years are eligible if the co-morbidity score is ≤ 2
  • Organ Function

    • Cardiac: Left ventricular ejection fraction > 35%; absence of decompensated congestive heart failure; absence of uncontrolled arrhythmia
    • Pulmonary: DLCO > 30% of predicted; absence of O2 requirements
    • Hepatic: ALT, AST, alkaline phosphatase and bilirubin < 5 x upper limit of normal
    • Renal: Creatinine ≤ 2 mg/dl (patients with a creatinine > 1.2 or history of renal dysfunction must have calculated glomerular filtration rate (GFR) > 40 mL/min/1.73m2)
    • If recent mold infection e.g. Aspergillus - must have minimum of 30 days of appropriate treatment before transplant and infection controlled and be cleared by Infectious Disease.
    • The following conditions must be met:

      • If prior myeloablative autologous transplant, must be > 3 months but ≤ 12 months from transplant OR have received at least 2 cycles of multi-agent or highly immunosuppressive chemotherapy (i.e. induction for acute leukemia) within the 3 months preceding this study. OR
      • If neither prior myeloablative autologous transplant ≤ 12 months from transplant nor have received at least 2 cycles of multi-agent or highly immunosuppressive chemotherapy (i.e. induction for acute leukemia) within the 3 months preceding this study, patients are eligible as long as they receive equine anti-thymocyte globulin as part of the conditioning regimen.

Exclusion Criteria:

  • Patients who have an available, medically suitable, 5-6/6 HLA-A, B, DRB1 matched sibling donor
  • Patients who are eligible for autologous transplantation
  • Prior allogeneic transplant
  • Acquired or inherited bone marrow failure syndromes such as aplastic anemia and Fanconi anemia
  • Pregnant or breast feeding
  • Evidence of HIV infection or known HIV positive serology
  • Current uncontrolled serious infection
  • Active central nervous system malignancy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00963872

Locations
United States, Minnesota
University of Minnesota Medical Center - Fairview
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Principal Investigator: Claudio G. Brunstein, MD, PhD Masonic Cancer Center, University of Minnesota
  More Information

No publications provided

Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT00963872     History of Changes
Other Study ID Numbers: 2008LS097, MT2008-15, 0809M46361, RC1HL099447
Study First Received: August 21, 2009
Last Updated: March 15, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Multiple Myeloma
Myelodysplastic Syndromes
Neoplasms, Plasma Cell
Preleukemia
Blood Protein Disorders
Bone Marrow Diseases
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Precancerous Conditions
Vascular Diseases
Complement System Proteins
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Vidarabine
Alkylating Agents
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents

ClinicalTrials.gov processed this record on October 23, 2014