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)

Status

Terminated

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00963872

Enrollment

Registered

2009-08-24

Start date

2010-03-31

Completion date

2013-08-31

Last updated

2017-12-28

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Leukemia, Lymphoma, Multiple Myeloma, Myelodysplastic Syndromes

Brief summary

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.

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.

Interventions

DRUGcyclophosphamide

50 mg/kg intravenously (IV) over 2 hours on Day -6.

DRUGfludarabine phosphate

40 mg/m\^2 over 1 hour on Days -6 through -2.

RADIATIONTotal body irradiation

200 cGy on Day -1

BIOLOGICALUmbilical 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.

BIOLOGICALUnmanipulated UCB Unit

On Day 0, the unmanipulated UCB unit will be infused FIRST through a central line without in-line filtration per institutional guidelines.

Study design

Allocation

RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

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.

Design outcomes

Primary

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

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

Countries

United States

Participant flow

Recruitment details

Subjects were recruited at the time of clinic visit or hospitalization. Patients that were considered for umbilical cord transplant were approached with the study.

Pre-assignment details

Subjects that were eligible for umbilical cord transplant were considered for the study.

Participants by arm

Arm	Count
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.	25
Complement Fragment A - Larger Cell Dose Patients who received complement fragment 3a (C3a) priming of the UCB unit with the larger cell dose.	6
Total	31

Baseline characteristics

Characteristic	Complement Fragment A - Larger Cell Dose	Complement Fragment 3A - Small Cell Dose	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	1 Participants	6 Participants	7 Participants
Age, Categorical Between 18 and 65 years	5 Participants	19 Participants	24 Participants
Age, Continuous	50 years STANDARD_DEVIATION 15.7	55 years STANDARD_DEVIATION 13	54 years STANDARD_DEVIATION 13.4
Region of Enrollment United States	6 participants	25 participants	31 participants
Sex: Female, Male Female	2 Participants	9 Participants	11 Participants
Sex: Female, Male Male	4 Participants	16 Participants	20 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	24 / 24	5 / 5
serious Total, serious adverse events	21 / 24	5 / 5

Outcome results

Primary

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.

Time frame: Day 180