Clinical trial NCT00376519: Umbilical Cord Blood T-Regulatory Cell Infusion Followed by Donor Umbilical Cord Blood Transplant in Treating Patients With High-Risk Leukemia or Other Hematologic Diseases
Official title: Umbilical Cord Blood Transplant With Co-Infusion of T Regulatory Cells
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Graft Versus Host Disease
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Secondary Myelofibrosis
Keywords: graft versus host disease
adult acute lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
secondary acute myeloid leukemia
refractory anemia with excess blasts
myelodysplastic syndromes
chronic myelogenous leukemia
refractory anemia
prolymphocytic leukemia
stage IV adult lymphoblastic lymphoma
recurrent adult Burkitt lymphoma
stage I adult Burkitt lymphoma
stage III adult Burkitt lymphoma
stage IV adult Burkitt lymphoma
follicular lymphoma
mantle cell lymphoma
chronic idiopathic myelofibrosis
secondary myelofibrosis
refractory chronic lymphocytic leukemia
recurrent small lymphocytic lymphoma
recurrent marginal zone lymphoma
marginal zone lymphoma
diffuse large cell lymphoma
anaplastic large cell lymphoma
lymphoblastic lymphoma
immunoblastic large cell lymphoma
multiple myeloma
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2006-09-15
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving chemotherapy, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor umbilical cord blood stem cell transplant helps stop the growth of cancer or abnormal cells and prepares the patient's bone marrow for the stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer or abnormal cells (graft-versus-tumor effect). Giving an infusion of the donor's T-regulatory cells before the transplant may help increase this effect. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase I trial is studying the side effects and best dose of umbilical cord blood T-regulatory cell infusion followed by donor umbilical cord blood transplant in treating patients with high-risk leukemia or other hematologic diseases.

Detailed description: OBJECTIVES:

Primary

* Determine the maximum tolerated dose of umbilical cord blood (UCB)-derived CD4- and CD25-positive T-regulatory (Treg) cell infusion followed by double unrelated donor UCB transplantation in patients with high-risk leukemia or other hematologic diseases.

Secondary

* Determine the speed of neutrophil and platelet recovery at day 42 in these patients.
* Determine the incidence of "double chimerism" (e.g., engraftment of both UCB units) at day 21 in these patients.
* Determine the risk of severe grade III-IV acute graft-versus-host disease (GVHD) at day 100 in these patients.
* Determine the risk of chronic GVHD at 1 year post transplantation in these patients.
* Determine the probability of survival at 100 days and 1 year post transplantation in these patients.

OUTLINE: This is an open-label, dose-escalation study of CD4- and CD25-positive umbilical cord blood (UCB)-derived T-regulatory cells (Treg).

* Preparative therapy: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -9 to -7 and cyclophosphamide IV over 2 hours on days -8 and -7 (1 hour after fludarabine infusion). Patients then undergo total-body irradiation (TBI) twice daily on days -5 to -2.
* UCB-derived Treg infusion: Patients receive UCB-derived Treg cells IV on day -1.
* Double unrelated donor UCB transplantation: Patients undergo double unrelated donor UCB transplantation by IV infusion on day 0.
* Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours or orally 2 or 3 times daily beginning on day -3 and continuing until day 100, followed by a taper to day 180, in the absence of GVHD. Patients also receive mycophenolate mofetil (MMF) orally or IV twice daily on days -3 to 30 or 7 days after engraftment, whichever is later, in the absence of acute GVHD\*. If no donor engraftment occurs, MMF may be continued at the discretion of the attending physician.

NOTE: \*If the patient has acute GVHD requiring systemic therapy, MMF may be stopped 7 days after GVHD is controlled (e.g., resolution of skin rash, vomiting, and diarrhea).

Cohorts of 3-6 patients receive escalating doses of UCB-derived Treg cells until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience nonhematologic dose-limiting toxicity within 48 hours of Treg cell infusion. At least 6 patients are treated at the MTD.

Eligibility criteria: Inclusion Criteria:

Patient and Donor Demographic Criteria

* Patient must be 18-45 years of age.
* Patients must have three partially HLA matched UCB units. Units identified as the HSC source must be HLA matched at 4-6 HLA- A and B (at low to intermediate resolution) and DRB1 (at high resolution), and the units must be HLA matched at 4-6 HLA- A, B, DRB1 antigens with each other. Total cryopreserved HSC graft cell dose must be \>2.5 x 107 nucleated cells per kilogram recipient body weight. Also, the two umbilical cord blood (UCB) units must be ABO-matched.
* The UCB unit identified as the Treg source must be HLA matched at 4-6 HLA antigens with the patient (without an HLA or ABO matching criterion with the UCB HSC source).

Disease Criteria

* Patients must have a hematological malignancy as listed below:

  * Acute myelogenous leukemia: high risk CR1 (as evidenced by preceding myelodysplastic syndrome (MDS), high risk cytogenetics such as those associated with MDS or complex karyotype, or \>2 cycles to obtain complete remission (CR); second or greater CR. Must be in remission by morphology (\<5% blasts within normocellular marrow).
* Acute lymphocytic leukemia: high risk CR1 as evidenced by high risk cytogenetics \[t(9;22), t (1:19), t(4;11) or other MLL rearrangements\] or \> 1 cycle to obtain CR; second or greater CR.
* Chronic myelogenous leukemia resistant to imatinib therapy
* Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt) or refractory anemia with severe pancytopenia or high risk cytogenetics. Blasts must be \< 10% by a representative bone marrow aspirate morphology (otherwise induction chemotherapy to achieve \< 10% blasts is required pre-transplant).
* Advanced myelofibrosis
* Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma or follicular lymphoma that have progressed after at least two prior therapies. Patients with bulky disease (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant.
* Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy in CR1+ or PR1+.
* Large cell non-Hodgkins lymphoma (NHL) \> CR2/\> PR2. Patients in CR2/PR2 with initial short remission(\<6 months) are eligible.
* Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade NHL after initial therapy if stage III/IV in CR1/PR1 or after progression if stage I/II \<1 year.
* Multiple myeloma beyond PR2. Patients with chromosome 13 abnormalities, first response lasting less than 6 months, or β-2 microglobulin \> 3 mg/L, may be considered for this protocol after initial therapy.
* Recipients will have a Karnofsky score \> 80% and have acceptable organ function ie creatinine \< 2.0, bilirubin, AST/ALT, ALP \< 2 x normal, pulmonary function \> 50% normal, left ventricular ejection fraction \> 45%. Note: All patients with a creatinine \> 1.2 or a history of renal dysfunction must have creatinine clearance (must be \> 40 ml/min to be eligible).
* Recipients will sign informed consent approved by the Committee on the Use of Human Subjects at the University of Minnesota.

Exclusion Criteria:

* Pregnant or breastfeeding
* Evidence of HIV infection or known HIV positive serology
* Current active infection
* Available HLA matched sibling donor.
* CML in active blast crisis

Primary outcomes:
measure: Maximum tolerated dose of T-regulatory cells
timeFrame: Within 24 Hours
Secondary outcomes:
measure: Incidence of neutrophil recovery
timeFrame: Day 42
measure: Incidence of double chimerism
timeFrame: Day 21
measure: Incidence of grades II-IV and III-IV acute graft-versus-host disease (GVHD)
timeFrame: Day 100
measure: Incidence of chronic graft-versus-host disease
timeFrame: 1 Year
measure: Survival
timeFrame: Day 100 and 1 Year
measure: Incidence of Platelet Recovery
timeFrame: Day 180
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center at University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Claudio G. Brunstein, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: