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

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)

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.

Study Overview

• Status: Terminated
• Conditions: Lymphoma; Myelodysplastic Syndromes; Leukemia; Multiple Myeloma
• Intervention / Treatment: Radiation: Total body irradiation; Drug: cyclophosphamide; Drug: fludarabine phosphate; Biological: Umbilical cord blood unit with C3a fragment; Biological: Unmanipulated UCB Unit

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center - Fairview

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Radiation: Total body irradiation; 200 cGy on Day -1; Drug: cyclophosphamide; 50 mg/kg intravenously (IV) over 2 hours on Day -6.; Other Names: Cytoxan; Drug: fludarabine phosphate; 40 mg/m^2 over 1 hour on Days -6 through -2.; Other Names: Fludara; 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.	Radiation: Total body irradiation; 200 cGy on Day -1; Drug: cyclophosphamide; 50 mg/kg intravenously (IV) over 2 hours on Day -6.; Other Names: Cytoxan; Drug: fludarabine phosphate; 40 mg/m^2 over 1 hour on Days -6 through -2.; Other Names: Fludara; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With the Complement 3a (C3a) Unit Predominating	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.	Day 180

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neutrophil Engraftment	Achieving 500 neutrophils/uL by day 42.	Day 42
Donor Chimerism in Blood	Percentage of donor DNA present in the peripheral blood	Day 28
Incidence of Grades II-IV Graft-vs-host Disease	Development of graft-versus-host disease through day 100.	Day 0 through Day 100
Non-Relapse Mortality	Deaths not due to relapse.	Day 180
Overall Survival	Survival (alive) from transplantation to last follow-up.	Day 360
Bone Marrow Chimerism	Percentage of donor DNA in the bone marrow.	Day 21
Chronic Graft-Versus-Host Disease	Patients who developed chronic graft-versus-host disease.	Day 360
Relapse of Disease	Patients who developed disease relapse after transplantation.	Day 360
Disease Progression	Patients who developed disease progression after transplantation.	Day 360
Platelet Recovery	Number of patients with >20,000 platelets/uL by day 180	Day 180
Donor Chimerism in Blood	Percentage of donor DNA present in the peripheral blood	Day 60
Incidence of Grades III-IV Graft-vs-host Disease	Development of graft-versus-host disease by day 100.	0 to 100 days
Non-relapse Mortality	Deaths not due to relapse.	Day 360
Overall Survival at Day 720	Survival (alive) from transplantation to last follow-up at day 720.	720 days
Relapse of Disease	Patients who developed disease relapse after transplantation.	Day 720
Disease Progression	Patients who developed disease progression after transplantation.	Day 720
Donor Chimerism	Percentage of donor DNA in the bone marrow.	Day 100
Donor Chimerism	Percentage of donor DNA in the bone marrow.	Day 180
Donor Chimerism	Percentage of donor DNA in the bone marrow.	Day 360

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Claudio G. Brunstein, MD, PhD, Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: August 21, 2009
• First Submitted That Met QC Criteria: August 21, 2009
• First Posted (Estimate): August 24, 2009

Study Record Updates

• Last Update Posted (Actual): December 28, 2017
• Last Update Submitted That Met QC Criteria: December 3, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Myelodysplastic Syndromes; Multiple Myeloma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine; Fludarabine phosphate
• Other Study ID Numbers: 2008UC097; MT2008-15 (Other Identifier: Blood and Marrow Transplantation Program); 0809M46361 (Other Identifier: IRB, University of Minnesota); RC1HL099447 (U.S. NIH Grant/Contract)