T-Regulatory Cell Infusion Post Umbilical Cord Blood Transplant in Patients With Advanced Hematologic Cancer

Phase I Study of Infusion of Umbilical Cord Blood (UCB) Derived CD25+CD4+ T-Regulatory (Treg) Cells After Nonmyeloablative Cord Blood Transplantation

RATIONALE: Giving chemotherapy, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor umbilical cord blood transplant helps 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). Giving an infusion of the donor's T-regulatory cells after the transplant may decrease this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. However, the donor immune system may also react against the recipient's tissues (graft-versus-host disease).

PURPOSE: This phase I trial is studying the side effects and best dose of donor T-regulatory cells after an umbilical cord blood transplant in treating patients with advanced hematologic cancer or other disorder.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Myelodysplastic Syndromes; Leukemia; Multiple Myeloma; Plasma Cell Neoplasm
• Intervention / Treatment: Biological: umbilical cord blood transplantation; Drug: Allopurinol; Drug: fludarabine phosphate; Drug: Cyclophosphamide; Radiation: Total body irradiation; Biological: Treg infusion; Drug: Sirolimus

Detailed Description

OBJECTIVES:

Primary

• Determine the maximum tolerated dose (MTD) of umbilical cord blood (UCB)-derived T-regulatory (Treg) cells.

Secondary

• Estimate the proportion of patients with detectable circulating Treg cells at 0, 1, 3, 7, and 14 days after infusion.
• Estimate the risk of grades II-IV and III-IV acute graft versus host disease (GVHD) at day +100 with the infusion of Treg cells.
• Estimate the proportion of patients with sustained donor engraftment.
• Estimate the proportion of patients with double chimerism at 6 months and 1 year.
• Determine the speed and cumulative incidence of neutrophil recovery by day 42 and platelet recovery by 6 months after UCB transplantation.
• Estimate the risk of chronic GVHD at 1 year.
• Estimate the probability of disease-free survival at 100 days and 1 year.
• Estimate the risk of fungal and viral infections at 1 year
• Estimate the risk of relapse at 1 year
• Characterize the pattern of immune cell recovery over 1 year

OUTLINE: This is a dose-escalation study of umbilical cord blood (UCB)-derived T-regulatory (Treg) cells. Patients receive nonmyeloablative UCB transplantation and post-transplant immunosuppression as in protocol UMN-2005LS036 (without antithymocyte globulin during conditioning regimen).

• Nonmyeloablative conditioning and UCB transplantation: Patients receive allopurinol on days -7 to day 0, fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on day -6; undergo total-body irradiation (TBI) once on day -1; and undergo UCB transplantation on day 0.
• Immunosuppression therapy: Beginning on day -3 and continuing until day +100, patients receive sirolimus intravenously (IV) with 8-12 mg oral loading dose followed by a single dose of 4mg/day with a target serum concentration of 3-12 mg/mL with a taper until day +180. Patients also receive mycophenolate mofetil IV or orally every 8 hours on days -3 to +30.
• Radiation therapy: total body irradiation is administered on Day -1 of 200 cGy.
• UCB Treg cell infusion: Patients receive escalating doses of UCB-derived CD4+ CD25+ Treg cells IV on day +1 (and Day +15 for dose level 5 only) until the maximum tolerated dose is obtained.

After completion of study treatment, patients are followed at day 180, 360, and 720.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center at University of Minnesota

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:

• Ages 18 to 75 years old

• Eligible for and co-enrolled on protocol UMN-2005LS036, for treatment of any of the following advanced hematologic malignancies:

  • Acute leukemias in complete remission (high risk CR1 or subsequent CR); chronic myelogenous leukemia (except refractory blast crisis); myelodysplastic syndrome with severe pancytopenia or complex cytogenetics, large-cell lymphoma, Hodgkin's lymphoma and multiple myeloma, chronic lymphocytic leukemia/small lymphocytic lymphoma, marginal zone b-cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia may be eligible after initial therapy.
• Have three partially HLA matched umbilical cord blood (UCB) units (1-2 units for UCB transplantation per MT2005-02 and 1 unit for the Treg cell infusion.)
• Adequate organ function

Exclusion Criteria:

• Patients not exposed to highly immunosuppressive single agent or multi-agent chemotherapy within 3 months, or an ablative preparative regimen for autologous hematopoietic stem cell transplant (HCT) within 1 year.
• Pregnancy or breastfeeding
• Current active serious infection
• Evidence of human immunodeficiency virus (HIV) or known HIV positive serology
• Patients with acute leukemia in morphologic relapse/persistent disease defined as >5% blasts in a > or = 15% cellular 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 in refractory blast crisis.
• Active central nervous system malignancy.

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: UCB post-transplant Treg Cell Infusion; Includes patients with high risk malignancy receiving allopurinol, fludarabine phosphate, cyclophosphamide, sirolimus, total body irradiation, double umbilical cord blood transplantation and Treg infusion cells after transplant. Patients will receive differing dose levels as they are entered and assigned to determine the maximum tolerated dose.

Biological: umbilical cord blood transplantation; Infusion of umbilical cord blood; Other Names: UCB transplant; Drug: Allopurinol; Administration begins Day -7 through Day 0, tablet or powder prescribed on an individual basis.; Other Names: Zyloprim; Drug: fludarabine phosphate; 40 mg/m^2 intravenously over 1 hour on Days -6, -5, -4, -3, -2; Other Names: Fludara; Drug: Cyclophosphamide; 50 mg/kg intravenous over 2 hours on Day -6; Other Names: Cytoxan; Radiation: Total body irradiation; 200 cGy on Day -1; Other Names: radiation; Biological: Treg infusion; Infusion of T regulatory cells on Day +1 (also Day +15 for Dose level 5 only). Dose escalation ranges include 1, 3, 10, 30, 100, 300 1000, and 300 x 10^5 Treg/kg.; Other Names: Treg cells; Drug: Sirolimus; Beginning on day -3 and continuing until day +100, patients receive sirolimus intravenously (IV) with 8-12 mg oral loading dose followed by a single dose of 4mg/day with a target serum concentration of 3-12 mg/mL with a taper until day +180.; Other Names: Rapamune®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose	Nine dose levels of CD4+CD25+ Treg are scheduled with the doses being 1, 3, 10, 30, 30+30, 100, 300, 1000, and 3000 x 10^5 Treg/kg recipient body weight. The dose escalation will proceed in cohorts of one patient until the first dose limiting toxicity (DLT) is observed.	48 Hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with detectable Treg cells	determined by polymerase chain reaction (PCR) and flow cytometry	Days 0, +1, +3, +7, and +14 after Treg cell infusion
Number of Patients with grade II-IV and grade III-IV acute graft versus host disease (GVHD)	Patients will be assessed weekly for GVHD 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. Incidence of grades II-IV and grades III-IV GVHD by day 100 will be monitored.	Day 100
Number of patients with sustained donor engraftment		Day 100
Number of patients with double chimerism		6 Months and 1 Year
Incidence of neutrophil recovery after umbilical cord blood (UCB) transplantation		Day 42
Number of Patients with Chronic Graft Versus Host Disease (GVHD)		1 Year
Number of Patients with disease-free survival		Day 100 and 1 Year
Number of Patients with Fungal and Viral Infections	Count of reported infections.	1 Year
Incidence of platelet recovery after umbilical cord blood (UCB)		6 Months After Transplant
Number of Patients with Disease Relapse		1 Year
Percent of Patients with Immune Cell Recovery		1 Year

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Margaret L. MacMillan, MD, Masonic Cancer Center, University of Minnesota; Principal Investigator: Claudio G. Brunstein, MD, PhD, Masonic Cancer Center, University of Minnesota

Publications and helpful links

General Publications

• Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P, McGlave PB, Blazar BR, Wagner JE. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011 Jan 20;117(3):1061-70. doi: 10.1182/blood-2010-07-293795. Epub 2010 Oct 15.

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2007
• Primary Completion (Actual): September 25, 2014
• Study Completion (Actual): April 16, 2015

Study Registration Dates

• First Submitted: January 10, 2008
• First Submitted That Met QC Criteria: January 18, 2008
• First Posted (Estimate): January 28, 2008

Study Record Updates

• Last Update Posted (Actual): December 2, 2017
• Last Update Submitted That Met QC Criteria: November 29, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: B-cell lymphoma; Hodgkin lymphoma; recurrent mantle cell lymphoma; anaplastic large cell lymphoma; multiple myeloma; prolymphocytic leukemia; follicular lymphoma; diffuse large cell lymphoma; small lymphocytic lymphoma; chronic myelogenous leukemia; advanced chronic lymphocytic leukemia
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Lymphoma; Myelodysplastic Syndromes; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia; Plasmacytoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Sirolimus; Allopurinol
• Other Study ID Numbers: 2007LS022; MT2006-01 (Other Identifier: Blood and Marrow Transplantation Program); 0701M00303 (Other Identifier: IRB, University of Minnesota)