Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD
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| ClinicalTrials.gov Identifier: NCT00914940 |
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Recruitment Status :
Terminated
(Did not reach one of the primary endpoints of decreased total acute GVHD)
First Posted : June 5, 2009
Results First Posted : August 20, 2020
Last Update Posted : August 20, 2020
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Graft Versus Host Disease Leukemia Myelodysplastic Syndromes | Drug: Fludarabine Phosphate Drug: Tacrolimus Drug: Thiotepa Radiation: Total-Body Irradiation (TBI) Other: Magnetic Affinity Cell Sorting Procedure: Peripheral Blood Stem Cell Transplantation Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation | Phase 2 |
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.
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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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 41 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | December 17, 2009 |
| Actual Primary Completion Date : | December 1, 2019 |
| Actual Study Completion Date : | May 26, 2020 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm 1
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. |
Drug: Fludarabine Phosphate
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.
Other Names:
Drug: Tacrolimus 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. Other Names:
Drug: Thiotepa 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).
Other Names:
Radiation: Total-Body Irradiation (TBI) TBI will be given as 165 cGy fractions twice per day x 4 days - total dose 1320cGy (days -10 to -7).
Other Name: TBI Other: Magnetic Affinity Cell Sorting Device
Other Name: Magnetic-Activated Cell Sorter (CliniMACS, Miltenyi) Procedure: Peripheral Blood Stem Cell Transplantation Patient will undergo a PBSC transplantation
Other Names:
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation |
- Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD [ Time Frame: Within 360 days of transplant ]Number of participants with aGVHD and severity of aGVHD within the first 360 days post-transplant as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Acute GVHD is graded by standard criteria, and all suspected cases of acute GVHD will be confirmed histologically by biopsy of an affected organ. The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract. Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening.
- Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC Transplant [ Time Frame: Up to 5 years post transplant ]Graft failure is defined as either a failure to reach an ANC of >500/uL for 3 consecutive days by day 28 post-transplant, or an irreversible decrease in ANC <100 after an established donor graft, unless there is a reasonable explanation such as a viral infection or drug effect that may be responsible for a reversible decrease in ANC.
- Transplant-related Mortality by Day 100 [ Time Frame: Transplant to day 100 ]Number of participants who died due to transplant-related issues within the first 100 days of transplant
- Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC Transplant [ Time Frame: Up to 5 years post transplant ]Relapse is defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology. Testing for recurrent malignancy in the blood and bone marrow performed by monitoring the CBC and bone marrow at Day 28, 58, 80, 360, and as needed for suspected relapse.
- Number of Participants With Chronic GVHD [ Time Frame: Up to 5 years post transplant ]Chronic GVHD measured by meeting NIH criteria and treated with immune suppression
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| Ages Eligible for Study: | 14 Years to 55 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
DISEASE CHARACTERISTICS:
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00914940
| United States, Connecticut | |
| Yale University School of Medicine/Yale New Haven Hospital | |
| New Haven, Connecticut, United States, 06520 | |
| United States, Washington | |
| Fred Hutchinson Cancer Research Center | |
| Seattle, Washington, United States, 98109-1024 | |
| Principal Investigator: | Marie Bleakley, MD | Fred Hutchinson Cancer Center | |
| Principal Investigator: | Warren Shlomchik, MD | Yale University School of Medicine/Yale New Haven Hospital |
Documents provided by Fred Hutchinson Cancer Center:
| Responsible Party: | Fred Hutchinson Cancer Center |
| ClinicalTrials.gov Identifier: | NCT00914940 |
| Other Study ID Numbers: |
2222.00 P30CA015704 ( U.S. NIH Grant/Contract ) P01CA018029 ( U.S. NIH Grant/Contract ) IR-6907 ( Other Identifier: FHCRC IRB ) CDR0000644201 ( Registry Identifier: NCI PDQ ) 0903004832 ( Other Identifier: HIC Protocol Number ) NCI-2010-00713 ( Registry Identifier: NCI / CTRP ) RG2810004 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ) |
| First Posted: | June 5, 2009 Key Record Dates |
| Results First Posted: | August 20, 2020 |
| Last Update Posted: | August 20, 2020 |
| Last Verified: | July 2020 |
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graft versus host disease adult acute lymphoblastic leukemia in remission recurrent adult acute lymphoblastic leukemia childhood acute lymphoblastic leukemia in remission recurrent childhood acute lymphoblastic leukemia adult acute myeloid leukemia in remission recurrent adult acute myeloid leukemia adult acute myeloid leukemia with 11q23 (MLL) abnormalities adult acute myeloid leukemia with inv(16)(p13;q22) adult acute myeloid leukemia with t(15;17)(q22;q12) |
adult acute myeloid leukemia with t(16;16)(p13;q22) adult acute myeloid leukemia with t(8;21)(q22;q22) childhood acute myeloid leukemia in remission recurrent childhood acute myeloid leukemia childhood myelodysplastic syndromes previously treated myelodysplastic syndromes refractory anemia with excess blasts de novo myelodysplastic syndromes secondary myelodysplastic syndromes |
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Leukemia Preleukemia Myelodysplastic Syndromes Graft vs Host Disease Syndrome Disease Pathologic Processes Neoplasms by Histologic Type Neoplasms Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Immune System Diseases Fludarabine Fludarabine phosphate |
Thiotepa Tacrolimus Antineoplastic Agents Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Calcineurin Inhibitors Enzyme Inhibitors Antineoplastic Agents, Alkylating Alkylating Agents Myeloablative Agonists |