T-Regulatory Cell and CD3 Depleted Double Umbilical Cord Blood Transplantation in Hematologic Malignancies

Phase 1

Withdrawn

• Conditions: Hematologic Malignancy; Acute Myeloid Leukemia; Chronic Lymphocytic Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia in Blast Crisis; Chronic Myeloproliferative Disease; Anemia, Refractory, With Excess of Blasts; Small Lymphocytic Lymphoma; Marginal Zone B-cell Lymphoma; Follicular Lymphoma
• Interventions: Biological: Treg cells; Biological: CD3+ Teff cells; Drug: Fludarabine; Drug: Cyclophosphamide; Radiation: Total body irradiation; Biological: Umbilical cord blood transplantation

• Registration Number: NCT01163201
• Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary

This is a unique dose-escalation trial that will titrate doses of umbilical cord blood (UCB) Treg and CD3+ Teff cells with the goal of infusing as many CD3+ Teff cells as possible without conferring grade II-IV acute graft-versus-host disease (GVHD).

In this study, the investigators propose to add UCB Treg and UCB CD3+ Teff cells to the two TCD UCB donor units with the goal of transplanting as many CD3+ Teff cells as possible without reintroducing risk of acute GVHD. The investigators hypothesize that Treg will permit the reintroduction of CD3+ Teff cells that will provide a bridge while awaiting HSC T cell recovery long term. The co-infusion of Treg will prevent GVHD without the need for prolonged pharmacologic immunosuppression.

Detailed Description

Based on prior studies, the first patient will start at lowest dose combination (3 x 10\^6/kg of Treg and 3 x 10\^6/kg of CD3+ Teff cells).

One patient will be entered at each level with a minimum of 35 days to observe the patient prior to moving to the next dose level. (1) If GVHD does not occur, a "successful step", then the CD3+ Teff cell dose will increase to the next higher level for the next patient; (2) If GVHD occurs, a "failed step", then Treg dose will increase to the next higher level for the next patient. It would take a minimum of 5 (if no GVHD) and maximum of 9 patients (if GVHD is observed at each level) to complete all Treg:CD3+ Teff cell combinations.

An additional 10 patients will be enrolled to verify that this reflects the optimal combination and evaluate its safety profile.

Study Timeline

• Study First Submitted: 2010-05-26
• Study First Submitted QC: 2010-07-14
• Study First Posted: 2010-07-15
• Study Start: 2014-01
• Primary Completion: 2015-01
• Study Completion: 2015-01
• Status Verified: 2017-11
• Last Update Submitted: 2017-11-29
• Last Update Posted: 2017-12-02

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Only patients requiring a double umbilical cord blood (UCB) transplant are to be considered for this study.

UCB Requirements

• Three UCB units are required - one for Treg production and two for UCB transplant. The unrelated UCB donors must be 4-6/6 HLA-A, B, DRB1 matched with the recipient (HLA matching using molecular techniques: A and B to antigen level resolution and DR to allele level resolution). Suitable UCB units will be selected according to the University Of Minnesota UCB Graft Selection Algorithm.
• Suitable UCB units must be ABO matched.

Disease Criteria:

• Patients aged 18 to 55 years

• Acute Myeloid Leukemia: with morphologically persistent disease in a representative bone marrow aspirate sample with ≤ 10% blasts after at least 1 cycles of chemotherapy (if patient refuses or is disqualified from alternative protocols), or in 3rd or higher complete remission (CR).

• Acute Lymphocytic Leukemia: with morphologically persistent disease in a representative bone marrow aspirate sample with ≤ 10% blasts after at least 1 cycles of chemotherapy, or in 3rd or higher CR

• Chronic Myelogenous Leukemia in Blast Crisis: with ≤10% residual blasts in the bone marrow aspirate after at least 1 cycle of induction chemotherapy in combination with a tyrosine kinase inhibitor (TKI)

• Refractory Anemia with Excess Blasts: (≤ 10%) in representative bone marrow aspirate sample of blasts after 1 cycle of induction chemotherapy. If treated with hypomethylating agents, patients are eligible if blast count is ≤ 10% after 4 cycles or evidence of stable or progressive disease after at least 2 cycles.

• Chronic Myeloproliferative Disease

• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Marginal Zone B-Cell Lymphoma or Follicular Lymphoma: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm

• Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Leukemia: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm

• Large Cell Non-Hodgkin's Lymphoma: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm

• Lymphoblastic Lymphoma, Burkitt's Lymphoma, and other High-Grade NHL: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm

• Performance Status, Age, and Organ Function

• Adequate performance status defined as a Karnofsky score ≥ 80%

• Adequate organ function defined as:

  • Renal: creatinine < 2.0 mg/dL,
  • Hepatic: bilirubin, AST/ALT, ALP < 5 x upper limit of normal,
  • Pulmonary function: DLCOcorr > 50% normal,
  • Cardiac: left ventricular ejection fraction > 45%

• Voluntary written informed consent signed before performance of any study-related procedure not part of normal medical care

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Exclusion Criteria

• Available medically suitable HLA-identical related donor
• Active infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days)
• 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 myeloablative transplant within the last 6 months
• Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation
• Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tositumomab (Bexxar) as part of their salvage therapy (not eligible for myeloablative umbilical cord blood transplant)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treg Plus CD3+Teff Treatment	Treg cells	Includes dose adjustment of T regulatory (Treg) and CD3+ T effector (CD3+ Teff) cells in recipients of double UCB transplantation
Treg Plus CD3+Teff Treatment	CD3+ Teff cells	Includes dose adjustment of T regulatory (Treg) and CD3+ T effector (CD3+ Teff) cells in recipients of double UCB transplantation
Treg Plus CD3+Teff Treatment	Total body irradiation	Includes dose adjustment of T regulatory (Treg) and CD3+ T effector (CD3+ Teff) cells in recipients of double UCB transplantation
Treg Plus CD3+Teff Treatment	Umbilical cord blood transplantation	Includes dose adjustment of T regulatory (Treg) and CD3+ T effector (CD3+ Teff) cells in recipients of double UCB transplantation
Treg Plus CD3+Teff Treatment	Cyclophosphamide	Includes dose adjustment of T regulatory (Treg) and CD3+ T effector (CD3+ Teff) cells in recipients of double UCB transplantation
Treg Plus CD3+Teff Treatment	Fludarabine	Includes dose adjustment of T regulatory (Treg) and CD3+ T effector (CD3+ Teff) cells in recipients of double UCB transplantation

Primary Outcome Measures

Name	Time	Method
Optimal Cell Dose Mixture	Day 0	Determine the optimal cell dose mixture of UCB T regulatory and CD3+ T effector cells without the development of grade II-IV acute GVHD

Secondary Outcome Measures

Name	Time	Method
Determine incidence of infusional toxicity	48 hours	reaction that occurs with 48 hours of product infusion
Incidence of neutrophil recovery	Day 42	Determine the incidence of neutrophil recovery (absolute neutrophil count ≥ 500/uL) at day 42
Incidence of double and single chimerism	Day +21, Day +180, 1 Year	Determine incidence of double and single unit chimerism at various time points
Incidence of Viral and Fungal Infections	1 Year	Determine incidence of viral and fungal infections at 1 year
1 Year Survival	1 Year	Estimate the probability of survival at 1 year
Incidence of Grade III-IV Acute Graft-Versus-Host Disease	Day 100	Determine the incidence of grade III-IV acute GVHD at day 100
Incidence of Treatment Related Death	6 Months	Determine the incidence of treatment related mortality (TRM) at 6 months
Incidence of Platelet Recovery	1 Year	Determine the incidence of platelet recovery (platelet count ≥ 50,000/uL) at 1 year
Incidence of Chronic Graft-Versus-Host Disease	1 Year	Determine the incidence of chronic GVHD at 1 year
Incidence of Relapse	1 Year	Determine the incidence of relapse at 1 year

Trial Locations

Locations (1)

Masonic Cancer Center, University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States