Clinical trial NCT01163201: T-Regulatory Cell and CD3 Depleted Double Umbilical Cord Blood Transplantation in Hematologic Malignancies
Official title: Optimization of the T Regulatory Cell and T Effector Cell Doses in Recipients of Double UCB Transplantation for Treatment of Hematological Malignancies
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Hematologic Malignancy
Acute Myeloid Leukemia
Acute Lymphocytic Leukemia
Chronic Myelogenous Leukemia in Blast Crisis
Anemia, Refractory, With Excess of Blasts
Chronic Myeloproliferative Disease
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Marginal Zone B-cell Lymphoma
Follicular Lymphoma
Lymphoplasmacytic Lymphoma
Mantle-Cell Lymphoma
Prolymphocytic Lymphoma
Large Cell Non-Hodgkin's Lymphoma
Lymphoblastic Lymphoma
Burkitt's Lymphoma
High Grade Non-Hodgkin's Lymphoma
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2010-07-15
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

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)

Primary outcomes:
measure: Optimal Cell Dose Mixture
timeFrame: Day 0
Secondary outcomes:
measure: Determine incidence of infusional toxicity
timeFrame: 48 hours
measure: Incidence of neutrophil recovery
timeFrame: Day 42
measure: Incidence of double and single chimerism
timeFrame: Day +21, Day +180, 1 Year
measure: Incidence of Viral and Fungal Infections
timeFrame: 1 Year
measure: 1 Year Survival
timeFrame: 1 Year
measure: Incidence of Grade III-IV Acute Graft-Versus-Host Disease
timeFrame: Day 100
measure: Incidence of Treatment Related Death
timeFrame: 6 Months
measure: Incidence of Platelet Recovery
timeFrame: 1 Year
measure: Incidence of Chronic Graft-Versus-Host Disease
timeFrame: 1 Year
measure: Incidence of Relapse
timeFrame: 1 Year
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Claudio Brunstein, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: