Reduced Intensity Double Umbilical Cord Blood Transplantation

A Phase II Study of Reduced Intensity Double Umbilical Cord Blood Transplantation Using Fludarabine, Melphalan, and Low Dose Total Body Radiation

This trial will use two cord blood units for transplantation using a reduced intensity regimen rather than using intense doses of chemotherapy and radiation therapy. Two cord blood units (double cord blood) are being used, as the numbers of blood cells in one unit are too few to allow successful growth of these cells.

Because the risk of infection, particularly virus infection, is high after double cord blood transplant, this study seeks to reduce the rise of virus infection by using a reduced intensity regimen without a medicine called antithymocyte globulin (ATG), as used in prior cord blood transplants. Subjects will receive two chemotherapy drugs, melphalan and fludarabine, and low dose of total body radiation (one treatment) instead of the ATG. The number of patients with virus infections in this study will be compared to our prior experience using the ATG.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma; Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma; Chronic Lymphocytic Leukemia; Acute Myelogenous Leukemia
• Intervention / Treatment: Drug: Fludarabine; Drug: Melphalan; Radiation: Total Body Radiation; Biological: Cord Blood

Detailed Description

Subjects will receive their transplants as in-patients.

• IV-Catheter

  • one or two IV catheters will be placed on the day of hospital admission

• Conditioning

  • Fludarabine IV six days before transplant (days -7, -6, -5. -4, -3, -2)
  • Melphalan IV (day -1)
  • Total body radiation on day 0 (same day as transplant)

• Immunosuppressive Therapy

  • Tacrolimus and sirolimus beginning day -3, daily for 6-9 months post-transplant. Given IV as in-patient, orally as out-patient

• Infusion of Cord Blood units

  • 2 cord blood units IV on Day 0 Routine post-transplant supportive care will be provided

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Hematologic malignancy for whom allogeneic stem cell transplantation is deemed clinically appropriate
• Appropriate candidate for reduced intensity regimen, according to the treating physician
• Lack of 6/6/ or 5/6 HLA-matched related, 8/8/ HLA-matched unrelated donor, or unrelated donor not available with a time frame necessary to perform a potentially curative stem cell transplant
• Able to comply with the requirements for care after allogeneic stem cell transplantation

Exclusion Criteria:

• Cardiac disease: symptomatic congestive heart failure or evidence of left ventricular dysfunction
• Pulmonary disease: symptomatic chronic obstructive lung disease, symptomatic restrictive lung disease
• Renal disease
• Hepatic disease
• Neurologic disease: symptomatic leukoencephalopathy, active CNS malignancy or other neuropsychiatric abnormalities believed to preclude transplantation
• HIV-positive
• Uncontrolled infection
• Pregnant or breast-feeding

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fludarabine/Melphalan/TBI; All patients receive same therapy	Drug: Fludarabine; 30 mg/m2/day IV x 6 days; Other Names: Fludara; Drug: Melphalan; 100 mg/m2/day IV x 1 day; Radiation: Total Body Radiation; 200 cGy on Day 0; Biological: Cord Blood; 2 cord blood units IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Clinically Significant Infection	The one year significant infection rate (infections requiring medical intervention) after double umbilical cord blood transplant using a novel conditioning regimen of fludarabine/melphalan/low dose total body radiation. The data is shown as the number of significant infections participants experienced during the first year, measured from the start of treatment.	1 Year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Time to Neutrophil Engraftment	The median number of days measured from the time of transplantation, until the first documented neutrophil engraftment. neutrophil engraftment is defined as the first of 3 consecutive days of absolute neutrophil count > 500 neutrophils per microliter of blood.	From the time of transplantation, until the time of neutrophil engraftment, median duration of 24 days
Median Time to Platelet Engraftment	The time to platelet engraftment is measured from the time of transplantation until the time of first documented platelet engraftment. Platelet engraftment is defined as a platelet count ≥ 20,000/µL for three consecutive measurements over three or more days. The first of the three days will be designated the day of platelet engraftment. Subjects must not have had platelet transfusions during the preceding 3 days or in the following 7 days after the day of engraftment, unless the platelet transfusion is being given specifically to achieve a platelet threshold to allow an elective invasive procedure, such as a central catheter removal.	From the time of transplantation, until the time of platelet engraftment, median duration of 52 days
Number of Participants With Primary Graft Failure	Primary graft failure is defined as the failure to achieve an absolute neutrophil count (ANC) >500/ µL by day 42, in the absence of relapse.	From the time of transplantation until 42 days post transplantation
Rates of Grade II-IV and Grade III-IV Acute Graft Versus Host Disease (GVHD) at 100 Days	Acute GVHD is assessed using Consensus Criteria: Organ Classifications: 0: No rash due to GVHD; Bilirubin < 2 mg/dL; < 500 mL diarrhea/ day; 1: Maculopapular rash < 25% of body surface; Bilirubin 2-3 mg/dL; 500 to 999 mL diarrhea/ day or persistent nausea with histologic evidence of GVHD in stomach/ duodenum; 2: Maculopapular rash 25-50% of body surface; Bilirubin 3.1-6 mg/dL; 1,000 to 1,499 mL diarrhea/ day; 3: Maculopapular rash > 50% of body surface; Bilirubin 6.1-15 mg/dL; 1,500 or more mL diarrhea/ day; 4: Generalized erythroderma with bullous formation; Bilirubin > 15 mg/dL; Severe abdominal pain with or without ileus Overall Clinical Grade: 0: No Stage 1-4 of any organ; I: Stage 1-2 rash and no liver or gut involvement; II: Stage 3 rash, or Stage 1 liver involvement, or Stage 1 gut involvement; III: None to Stage 3 skin rash with Stage 2-3 liver involvement, or Stage 2-4 gut involvement; IV: Stage 4 skin rash, or Stage 4 liver involvement	100 Days
The Rate of Chronic GVHD	Chronic Graft Versus Host Disease (GVHD) is assessed using the National Institutes of Health (NIH) consensus criteria.	From the time of transplantation until the time of chronic GVHD onset, up to 1 year
100-day Treatment Related Mortality	The percentage of treatment related participant deaths within 100 days of receiving umbilical cord blood transplantation. All deaths in the absence of relapse of the primary malignancy will be considered treatment related mortality.	100 Days
Immune Reconstitution - Median CD4 Count at 12 Months		1 Year
Relapse-free Survival	The percentage of participants that have not died or had disease progression by two years. Relapse is defined by either morphological or cytogenetic evidence of the original malignancy consistent with pre-transplant features.	2 years
Overall Survival	The percentage of participants alive at two years	2 years
1 Year Relapse Rate	The percentage of participants that relapsed within 12 months. Relapse is defined by either morphological or cytogenetic evidence of the original malignancy consistent with pre-transplant features.	1 year
Rate of Post-transplant Lymphoma	The number of participants that were found to have lymphoma post-transplant.	2.5 years
Median Thrombopoietin Levels After Transplant		30 Days

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Investigators: Principal Investigator: Zachariah DeFilipp, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: August 2, 2011
• First Submitted That Met QC Criteria: August 2, 2011
• First Posted (Estimate): August 3, 2011

Study Record Updates

• Last Update Posted (Actual): January 23, 2019
• Last Update Submitted That Met QC Criteria: December 29, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: lymphoma; NHL; aplastic anemia; leukemia; myelodysplastic disorder
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia, Lymphoid; Leukemia, B-Cell; Lymphoma; Multiple Myeloma; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Lymphocytic, Chronic, B-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Melphalan; Fludarabine
• Other Study ID Numbers: 11-085