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Graft Versus Host DiseasePhase 2NCT00914940

Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD

A Phase 2 study testing Fludarabine Phosphate, Tacrolimus and Thiotepa in people with Graft Versus Host Disease and Leukemia, run by Fred Hutchinson Cancer Center at 2 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 14 to 55 years
What is being tested?
Fludarabine Phosphate, Tacrolimus and Thiotepa
Could I receive a placebo?
No, everyone receives an active treatment
How many people
41 participants
Where
2 sitesUnited States
Study dates
17 Dec 2009to 26 May 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 14 to 55 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Yale University School of Medicine/Yale New Haven Hospital

    New Haven, Connecticut, 06520

  • Fred Hutchinson Cancer Research Center

    Seattle, Washington, 98109-1024

Other trials in United States

About this study

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

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.

Read the detailed 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.

Being tested
Fludarabine Phosphate, Tacrolimus, Thiotepa, Total-Body Irradiation (TBI), Magnetic Affinity Cell Sorting
Keywords
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
Medical subject headings
Graft vs Host Disease, Leukemia, Myelodysplastic Syndromes, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Myeloid, Acute, Congenital Abnormalities, Anemia, Refractory, with Excess of Blasts

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Fludarabine PhosphateDrug

    Also called 2-F-ara-AMP, Beneflur, Fludara

    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.

  • TacrolimusDrug

    Also called Advagraf, FK 506, Prograf, Protopic

    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.

  • ThiotepaDrug

    Also called Oncotiotepa, STEPA, TESPA, Tespamin

    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)Radiation

    Also called 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 SortingOther

    Also called Magnetic-Activated Cell Sorter (CliniMACS, Miltenyi)

    Device

  • Peripheral Blood Stem Cell TransplantationProcedure or surgery

    Also called PBPC transplantation, PBSC transplantation, Peripheral Blood Progenitor Cell Transplantation, Transplantation

    Patient will undergo a PBSC transplantation

  • Allogeneic Hematopoietic Stem Cell TransplantationProcedure or surgery

    Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation

  • T Cell-Depleted Hematopoietic Stem Cell TransplantationBiological

    Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation

Study groups in NCT00914940
Study groupRoleWhat they receive
Arm 1ExperimentalCONDITIONING: 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.
Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD

    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.

    Measured: Within 360 days of transplant

  2. Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC 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.

    Measured: Up to 5 years post transplant

Secondary outcomes (3)

  1. Transplant-related Mortality by Day 100

    Number of participants who died due to transplant-related issues within the first 100 days of transplant

    Measured: Transplant to day 100

  2. Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC 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.

    Measured: Up to 5 years post transplant

  3. Number of Participants With Chronic GVHD

    Chronic GVHD measured by meeting NIH criteria and treated with immune suppression

    Measured: Up to 5 years post transplant

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Jun 2009 (estimated)
  2. Study start17 Dec 2009
  3. Primary completion1 Dec 2019
  4. Study completion26 May 2020

Why it stopped: Did not reach one of the primary endpoints of decreased total acute GVHD

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
41 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00914940
Sponsor's protocol ID
2222.00
Other IDs
P30CA015704, P01CA018029, IR-6907, CDR0000644201, 0903004832, NCI-2010-00713, RG2810004
Status last verified
Jul 2020
First submitted
4 Jun 2009
Last updated
20 Aug 2020
Data monitoring committee
Yes

Publications

  • Bleakley M, Sehgal A, Seropian S, Biernacki MA, Krakow EF, Dahlberg A, Persinger H, Hilzinger B, Martin PJ, Carpenter PA, Flowers ME, Voutsinas J, Gooley TA, Loeb K, Wood BL, Heimfeld S, Riddell SR, Shlomchik WD. Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease. J Clin Oncol. 2022 Apr 10;40(11):1174-1185. doi: 10.1200/JCO.21.01755. Epub 2022 Jan 10.

    PubMed 35007144

  • Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S, Gooley TA, Sommermeyer F, Riddell SR, Shlomchik WD. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest. 2015 Jul 1;125(7):2677-89. doi: 10.1172/JCI81229. Epub 2015 Jun 8.

    PubMed 26053664

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Fludarabine Phosphate, Tacrolimus and Thiotepa in people with Graft Versus Host Disease and Leukemia, run by Fred Hutchinson Cancer Center at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 20 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 20 Aug 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00914940, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Aug 2020.

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