Overview

This trial is active, not recruiting.

Conditions graft versus host disease, leukemia, myelodysplastic syndromes
Treatments fludarabine phosphate, tacrolimus, thiotepa, total-body irradiation (tbi), magnetic affinity cell sorting, peripheral blood stem cell transplantation, allogeneic hematopoietic stem cell transplantation, t cell-depleted hematopoietic stem cell transplantation
Phase phase 2
Sponsor Fred Hutchinson Cancer Research Center
Collaborator National Cancer Institute (NCI)
Start date October 2009
End date August 2020
Trial size 60 participants
Trial identifier NCT00914940, 0903004832, 2222.00, CDR0000644201, IR-6907, P01CA018029, P30CA015704

Summary

RATIONALE: Allogeneic hematopoietic stem cell transplant (HSCT) is a treatment that can cure acute leukemia and myelodysplasia. After giving the patient chemotherapy and total body irradiation to stop the growth of cancer and remove the patient's diseased bone marrow, healthy stem cells from a donor are infused into the patient to replace the patient's bone marrow and make red and white blood cells and platelets. Unfortunately HSCT is often complicated by 'graft versus host disease' (GVHD) in which the transplanted cells from a donor can make an immune response against the body's normal cells and cause tissue damage and severe symptoms. Removing a subset of the donor T cells, called 'naive T cells', before transplant may reduce the frequency and intensity of GVHD.

PURPOSE: This phase II trial will determine whether the removal of the naive T cells from donor cells can decrease the rate and severity of graft-vs-host disease while preserving specific immunity against infections in patients with acute leukemia or advanced myelodysplastic syndromes.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Endpoint classification efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
CONDITIONING: Patients undergo total-body irradiation twice daily on days -10 to -7. Patients also receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine IV over 30 minutes on days -6 to -2. TRANSPLANTATION: Patients undergo infusion of CD34+ enriched allogeneic peripheral blood stem cells (PBSC) followed by CD45RA+ T-cell-depleted allogeneic PBSC on day 0. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Cohort A: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 50 followed by standard taper in the absence of grade II-IV acute GVHD. Cohort B: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 30 followed by rapid taper in the absence of grade II-IV acute GVHD.
fludarabine phosphate 2-F-ara-AMP
Fludarabine will be administered in a dose of 25 mg/m2/day IV over approximately 30 minutes for 5 consecutive days (day -6 to -2). The total dose of fludarabine will be 125 mg/m2.
tacrolimus Advagraf
Tacrolimus will be administered beginning on day -1 at a dose of 0.03 mg/kg/day by continuous IV infusion. For the first cohort of 35 patients, if there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus should then be tapered at the rate of approximately 5% of the day 50 dose each week for liquid, and 20% of the day 50 dose per month for capsules. In the second cohort of 25 patients if there is no evidence of grade II GVHD on or prior to day 30, tacrolimus should then be tapered at the rate of approximately 8% of the day 30 dose each week for liquid, and 33% of the day 30 dose per month for capsules.
thiotepa Oncotiotepa
Thiotepa will be administered in a dose of 5 mg/kg/day (adjusted body weight) IV over approximately 4 hours for 2 consecutive days (day -6 and day -5).
total-body irradiation (tbi) TBI
TBI will be given as 165 cGy fractions twice per day x 4 days - total dose 1320cGy (days -10 to -7).
magnetic affinity cell sorting Magnetic-Activated Cell Sorter (CliniMACS, Miltenyi)
Device
peripheral blood stem cell transplantation PBPC transplantation
Patient will undergo a PBSC transplantation
allogeneic hematopoietic stem cell transplantation
Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation
t cell-depleted hematopoietic stem cell transplantation
Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation

Primary Outcomes

Measure
Rate of grade II-IV acute graft-vs-host disease (GVHD)
time frame: Start of study to day 100
Rate of engraftment
time frame: Up to 5 years post transplant

Secondary Outcomes

Measure
Evaluation of recovery of T-cell immunity to pathogens
time frame: Start of study to day 100
Rate of transplant-related mortality at day 100
time frame: Start of study to day 100
Rate of relapse
time frame: Up to 5 years post transplant
Rate and severity of chronic GVHD
time frame: Up to 1 year post transplant

Eligibility Criteria

Male or female participants from 14 years up to 55 years old.

DISEASE CHARACTERISTICS: - Diagnosis of 1 of the following: - Acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) in first or subsequent remission - ALL or AML in relapse or primary refractory ALL or AML with a circulating blast count ≤ 10,000/mm^3 - Refractory anemia with excess blasts (RAEB) (RAEB-1 or RAEB-2) if the patient has received induction chemotherapy within the past 60 days - Appropriate candidate for allogeneic hematopoietic stem cell transplantation (HSCT) - No CNS involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiotherapy PATIENT CHARACTERISTICS: - Age 14-55 - Creatinine < 1.5 mg/dL - Cardiac ejection fraction > 45% - DLCO corrected > 60% of predicted - Total bilirubin < 2 times upper limit of normal (ULN) (unless attributed to Gilbert syndrome) - AST and ALT < 2 times ULN - Not pregnant or nursing - Fertile patients must use effective contraception during and for 12 months after transplantation - HIV negative - No co-existing disease (other than leukemia or RAEB) that would limit life expectancy to < 3 months - No uncontrolled infection that, in the opinion of the consulting infectious disease physician, would contraindicate myeloablative HSCT - No other medical condition that would contraindicate HSCT - No known hypersensitivity to tacrolimus PRIOR CONCURRENT THERAPY: - See Disease Characteristics - No prior HSCT - No concurrent participation in other experimental studies for the prevention of graft-vs-host disease DONOR CHARACTERISTICS: - Genotypic or phenotypic HLA-identical related donor - Able to donate peripheral blood stem cells - Age > 14 years - Applicable to male patients only: No female donors who have previously given birth to a male child or have had a pregnancy beyond the first trimester miscarriage or termination of pregnancy or nursing - No donors who have received blood transfusions - No CD45 Mutation with aberrant CD45RA isoform expression

Additional Information

Official title A Multi-center Phase II Study of Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD
Principal investigator Marie Bleakley, MD
Description OBJECTIVES: Primary - Estimate the probability of grades II-IV acute graft-vs-host disease (GVHD) in patients with acute leukemia or advanced myelodysplastic syndromes treated with CD45RA+ T-cell-depleted allogeneic peripheral blood stem cell transplantation and compare this to relevant historical experience. - Estimate the probability of graft failure in these patients. Secondary - Evaluate immune reconstitution and pathogen-specific T-cell reconstitution in these patients. - Estimate the probability of transplant-related mortality by day 100 in these patients. - Estimate the probability of relapse in these patients. - Estimate the probability and severity of chronic GVHD in these patients. OUTLINE: This is a multicenter study. - Myeloablative conditioning regimen: Patients undergo total body irradiation twice daily for 4 days (Days -10 to -7) Patients also receive thiotepa IV over 4 hours for 2 days (Days -6 and -5) and fludarabine phosphate IV over 30 minutes for 5 days (Days -6 to -2.) - Transplantation: Patients receive a CD34+ enriched allogeneic peripheral blood stem cell (PBSC) product followed by a CD45RA+ T-cell-depleted allogeneic PBSC product on day 0. - Graft-vs-host disease (GVHD) prophylaxis: Patients will receive Tacrolimus as per cohort 1. If the rate of grade II-IV acute GVHD in the first 35 patients is significantly reduced (compared to historical controls), subsequent patients are enrolled in cohort 2. - Cohort 1: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 50, followed by a standard taper in the absence of grade II-IV acute GVHD. - Cohort 2: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 30, followed by a rapid taper in the absence of grade II-IV acute GVHD. Patients are followed actively for at least 1 year post transplant.
Trial information was received from ClinicalTrials.gov and was last updated in January 2016.
Information provided to ClinicalTrials.gov by Fred Hutchinson Cancer Research Center.