Treg Cells for AGVHD in Non-myeloablative UCB Transplant

T Regulatory Cell for Suppression of Acute Graft-vs-Host-Disease in Recipients of a Non-Myeloablative Umbilical Cord Blood Transplantation for Treatment of Hematological Malignancies

This is a Simon's optimal two-stage phase II trial designed to estimate grade II-IV acute graft-versus-host disease (GVHD) after infusion of T regulatory (nTreg) in a fixed dose ratio to the combined CD3+ cell count of the two graft units in recipients of double UCB transplantation. The nTreg cells (manufactured from a 3rd cord blood unit) are infused on day 0 at least 1 hour after the 2nd unit of the double umbilical cord blood (UCB) transplant.

The nTreg cells require an 18 day (±2 days) lead time based on the planned transplant day. The combined CD3+ cell content from the two graft UCB units is enumerated upon thaw (day 0). The patient then receives the number of nTregs cells from the 3rd cord product to achieve a Treg:CD3+ cells ratio of 5:1. The nTreg cell dose depends on the CD3+ cell content of the two graft UCB graft units, but it will not exceed the highest dose level safely tested in the ongoing University of Minnesota phase I Treg dose escalation study MT 2006-01.

Study Overview

• Status: Withdrawn
• Conditions: Hematologic Malignancies
• Intervention / Treatment: Biological: T Regulatory cells; Drug: Fludarabine; Drug: Cyclophosphamide; Radiation: Total Body Irradiation

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Must be ≥18, but < 70 years of age with no matched 5/6 or 6/6 sibling donor - patients ≥ 70 and ≤ 75 years of age may be eligible if they have a Co-Morbidity score ≤ 2 (Appendix II)
• Three UCB units composing the graft will be selected according to the current University of Minnesota umbilical cord blood graft selection algorithm.
• Each UCB unit must be matched at 4-6 HLA-A, B, DRB1 antigens with the recipient. This may include 0-2 antigen mismatches at the A or B or DRB1 loci. Each unit must be a 4-6 HLA-A, B, DRB1 antigen match to each other, not necessarily at the same loci they are matched to the recipient.

• 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 versus early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse.

• Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR1) that is NOT considered favorable-risk as defined by the presence of at least one of the following:

  • Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), other MLL rearrangements
  • White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL) at diagnosis
  • Recipient age older than 30 years at diagnosis
  • Time to CR greater than 4 weeks

• Acute Myelogenous Leukemia (AML) in first complete remission (CR1) that is NOT considered as favorable-risk. Favorable risk is defined as having one of the following:

  • t(8,21) without CKIT mutation
  • inv(16) without CKIT mutation or t(16;16)
  • Normal karyotype with mutated NPM1 and not FLT-IND
  • Normal karyotype with double mutated CEBPA
  • APL in first molecular remission at end of consolidation
• Acute Leukemias in 2nd or subsequent CR

• Biphenotypic/Undifferentiated in first or subsequent CR, adult T-cell leukemia/lymphoma in first or subsequent complete remission (CR)

  • Burkitt's Lymphoma in CR2 or subsequent complete remission (CR)
  • Natural Killer Cell Malignancies
  • Chronic Myelogenous Leukemia: all types except refractory blast crisis. Chronic phase patients must have failed or been intolerant to at least one tyrosine-kinase inhibitor
  • Myelodysplastic Syndrome: any subtype including refractory anemia (RA) if severe pancytopenia or complex cytogenetics. Blasts must be less than 5%. If 5% or more requires induction therapy pre-transplant to reduce blast count to ≤5%.
  • Large-Cell Lymphoma, Hodgkin Lymphoma and Multiple Myeloma with chemotherapy sensitive disease that has failed or patients who are ineligible for an autologous transplant.
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Marginal Zone B-Cell Lymphoma, Follicular Lymphoma, which have progressed within 12 months of achieving a partial or complete remission. Patients who had remissions lasting > 12 months, are eligible 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.
  • Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Leukemia are eligible after initial therapy if chemotherapy sensitive.

Patients must have undergone an autologous transplant ≤ 12 months prior to allogeneic transplantation or have received multi-agent or immunosuppressive chemotherapy within 3 months of the preparative regimen.

• Adequate performance status defined as a Karnofsky score ≥ 70%

• Adequate organ function within 14 days (30 days for cardiac and pulmonary) of enrollment defined as:

  • Renal: creatinine < 2.0 mg/dL, for patient with a creatinine > 1.2 mg/dL or a history of renal dysfunction an estimated glomerular filtration rate > 40 mL/min/1.73 m2 is required
  • Hepatic: bilirubin, AST, ALT, alkaline phosphatase < 5 x upper limit of normal,
  • Pulmonary function: DLCOcorr > 40% normal,
  • Cardiac: left ventricular ejection fraction > 35%
• Voluntary written consent signed before performance of any study-related procedure not part of normal medical care

Exclusion Criteria:

• Untreated active infection at time of transplantation
• History of HIV infection
• Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy
• Prior allogeneic transplantation
• Less than 3 months from myeloablative conditioning for autologous transplantation

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TREG; T regulatory cells after non-myeloablative (using fludarabine, cyclophosphamide, and total body irradiation) umbilical cord transplant.	Biological: T Regulatory cells; Fixed dose of nTreg cells will be infused on day 0 of transplant after the umbilical cord blood cells; Other Names: nTreg; Treg; Drug: Fludarabine; Fludarabine 30mg/m^2 IV over 1 hour on days -6 through -2 from transplant; Other Names: Fludara; Drug: Cyclophosphamide; Cyclophosphamide 50 mg/kg IV over 2 hours on day -6 from transplant; Other Names: Cytoxan; Endoxan; Neosar; Revimmune; Procytox; Radiation: Total Body Irradiation; Total Body Irradiation (TBI) 200 cGy administered on day -1 in a single fraction will be given at a dose rate of 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.; Other Names: TBI
Experimental: Non-Myeloablative Only; Non-myeloablative (using fludarabine, cyclophosphamide, and total body irradiation) umbilical cord transplant.	Drug: Fludarabine; Fludarabine 30mg/m^2 IV over 1 hour on days -6 through -2 from transplant; Other Names: Fludara; Drug: Cyclophosphamide; Cyclophosphamide 50 mg/kg IV over 2 hours on day -6 from transplant; Other Names: Cytoxan; Endoxan; Neosar; Revimmune; Procytox; Radiation: Total Body Irradiation; Total Body Irradiation (TBI) 200 cGy administered on day -1 in a single fraction will be given at a dose rate of 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.; Other Names: TBI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of grade II-IV acute graft-versus-host disease	Determine if 3:1 ratio of Treg:CD3+ cells reduces the risk grade II-IV acute graft versus host disease of 20% by day 100 as compared to patients with hematological malignancy receiving same conditioning regimen and immunosuppression but no Tregs.	Day +100

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of double and single unit chimerism	Compare the incidence of double and single unit chimerism at day +100 between Treg and controls	Day +100
Incidence of grade III-IV acute graft-versus-host disease	Compare the incidence of grade III-IV aGVHD between Treg and controls	Day +100
Incidence of viral and fungal infections	Compare the incidence of viral and fungal infections at 1 year between Treg and controls	1 year
Survival	Compare the probability of survival at 1 year between Treg and controls	1 year
Incidence of neutrophil recovery	Compare the incidence of neutrophil recovery at day 42 between Treg and controls	Day 42
Incidence of treatment related mortality	Determine the incidence of treatment related mortality (TRM) at 6 months between Treg and controls	6 months
Incidence of platelet recovery	Compare the incidence of platelet recovery at 1 year between Treg and controls	1 year
Incidence of chronic GVHD	Compare the incidence of chronic GVHD at 1 year between Treg and controls	1 year
Incidence of relapse	Compare the incidence of relapse at 1 year between Treg and controls	1 year

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Collaborators: National Cancer Institute (NCI); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Claudio Brunstein, MD, PhD, University of Minnesota

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Anticipated): September 1, 2018
• Study Completion (Anticipated): September 1, 2018

Study Registration Dates

• First Submitted: March 26, 2014
• First Submitted That Met QC Criteria: April 16, 2014
• First Posted (Estimate): April 21, 2014

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: Multiple Myeloma; Myelodysplastic Syndrome; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Small Lymphocytic Lymphoma; Prolymphocytic Leukemia; Hodgkin Lymphoma; Burkitt's Lymphoma; Lymphoplasmacytic Lymphoma; Acute Leukemias; Natural Killer Cell Malignancies; Large-Cell Lymphoma; Marginal Zone B-Cell Lymphoma; Follicular Lymphoma:; Mantle-Cell Lymphoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: 2013LS091; MT2013-27 (Other Identifier: University of Minnesota Blood and Marrow Transplant Program); P01CA065493 (U.S. NIH Grant/Contract)