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Laboratory-Treated Lymphocyte Infusion After Haploidentical Donor Stem Cell Transplant

1 juli 2019 bijgewerkt door: Eva C. Guinan, MD, Dana-Farber Cancer Institute

Delayed Infusion of Ex Vivo Anergized Peripheral Blood Mononuclear Cells Following CD34 Selected Peripheral Blood Stem Cell Transplantation From a Haploidentical Donor for Patients With Acute Leukemia and Myelodysplasia

RATIONALE: Giving total-body irradiation and chemotherapy, such as thiotepa and fludarabine, before a donor stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving methylprednisolone and antithymocyte globulin before transplant and peripheral blood cells that have been treated in the laboratory after transplant may stop this from happening.

PURPOSE: This phase I trial is studying the side effects and best dose of laboratory-treated peripheral blood cell infusion after donor stem cell transplant in treating patients with hematologic cancers or other diseases.

Studie Overzicht

Gedetailleerde beschrijving

OBJECTIVES:

Primary

  • Establish the feasibility of delayed infusion of ex vivo anergized donor peripheral blood mononuclear cells (PBMC) after CD34 (cluster designation 34)-selected megadose haploidentical hematopoietic stem cell transplantation (HSCT) in patients with hematopoietic cancers or other diseases.
  • Determine the feasibility of collecting parental allogeneic stimulator cells to induce anergy to the nonshared donor-recipient haplotype in these patients.
  • Determine the feasibility of collecting donor PBMC as a source of T cells for ex vivo anergization.
  • Determine the number of transplanted individuals who meet the criteria for proceeding to delayed infusion of ex vivo anergized donor PBMC.
  • Establish the safety of delayed infusion of ex vivo anergized donor PBMC by establishing the maximum number of donor T cells that can be infused without unacceptable graft-versus-host disease.

Secondary

  • Evaluate, in vitro, the induction and specificity of alloantigen hyporesponsiveness in donor PBMC after ex vivo anergization.
  • Assess, in vitro, the function of immune cells engrafted in these patients.
  • Assess, in vitro, whether alloantigen hyporesponsive donor T cells are present in these patients.
  • Develop, preliminarily, in vitro data on the extent of pathogen-specific immunity and its rate of recovery.
  • Describe the patterns of opportunistic infections in these patients.

OUTLINE: This is a multicenter, dose-escalation study of ex vivo anergized allogeneic peripheral blood mononuclear cells (PBMC). Patients who are treated on any dose level except dose level 1 are stratified according to age (under 17 [pediatric] vs 17 and over [adult]).

  • Myeloablative conditioning regimen: Patients undergo total-body irradiation twice daily on days -11 to -9. Patients also receive thiotepa IV over 4 hours on days -8 and -7, fludarabine phosphate IV over 30 minutes on days -7 to -3, and anti-thymocyte globulin IV over 8 hours and methylprednisolone IV over 15-30 minutes on days -6 to -3.
  • Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo CD34-selected PBSCT on day 0.
  • Ex vivo anergized allogeneic PBMC infusion: If cells have engrafted and patients are free of active uncontrolled infection and graft-vs-host disease, patients undergo allogeneic or autologous PBMC infusion on day 35 or 42.

Cohorts of 3-8 patients receive escalating doses of ex vivo anergized allogeneic PBMCs until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of 5 or 3 of 8 patients experience dose-limiting toxicity.

After completion of study, patients are followed periodically for 2 years.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Studietype

Ingrijpend

Inschrijving (Werkelijk)

19

Fase

  • Fase 1

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studie Locaties

    • California
      • Los Angeles, California, Verenigde Staten, 90027-0700
        • Childrens Hospital Los Angeles
    • Florida
      • Gainesville, Florida, Verenigde Staten, 32610
        • University of Florida Health Science Center - Gainesville
    • Massachusetts
      • Boston, Massachusetts, Verenigde Staten, 02114
        • Massachusetts General Hospital
      • Boston, Massachusetts, Verenigde Staten, 02115
        • Children's Hospital Boston
      • Boston, Massachusetts, Verenigde Staten, 02115
        • Dana Farber Cancer Institute
    • Texas
      • Houston, Texas, Verenigde Staten, 77030-4009
        • M. D. Anderson Cancer Center at University of Texas

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

Niet ouder dan 50 jaar (Kind, Volwassen)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

DISEASE CHARACTERISTICS:

  • Diagnosis of 1 of the following:

    • Acute lymphocytic leukemia

      • In ≥ second complete remission (CR), defined as < 5% blasts in bone marrow (BM) and no active extramedullary disease OR in first CR with any of the following high risk features:

        • History of induction failure
        • Philadelphia chromosome positive
        • t(4;11) by cytogenetic analysis
        • Any infant with MLL rearrangements on cytogenetic analysis
      • No relapse with isolated extramedullary disease after completion of prior treatment
    • Acute myeloid leukemia

      • Failed induction therapy after < 3 courses
      • In ≥ second CR, defined as < 5% blasts in BM and no active extramedullary disease OR in first CR with any of the following high-risk features:

        • History of induction failure = 5q- or monosomy 7 cytogenetic findings
    • Any of the following myelodysplastic syndromes:

      • Refractory anemia (RA) with excess blasts (RAEB) with a high International Prognostic Scoring System (IPSS) score or score of intermediate-1(INT-1) or intermediate-2 (INT-2)
      • RAEB in transformation with INT-1, INT-2, or high IPSS score
      • RA with INT-2 score
  • Patients must have a healthy, related donor who is at least genotypically HLA-A, B, C, and DR haploidentical to the patient

    • No suitably matched family donor defined by genotypic or phenotypic identity for ≥ 5/6 A, B, or DR loci
    • No immediately available genotypically matched (6/6) unrelated marrow donor
    • No immediately available umbilical cord blood donor with suitable cell dose after a search ≥ 2 months
    • Patients whose medical condition is at high risk of deteriorating or whose disease is at high risk of progression during a donor search are eligible
  • Has a parent with a haplotype that is disparate from that of the donor for the haplotype shared by the patient and parent, but not shared by the patient and donor OR patient is able to donate sufficient autologous cells by peripheral blood draw or unstimulated leukapheresis
  • No active CNS disease

PATIENT CHARACTERISTICS:

  • Room air O_2 saturation > 95% unless the lungs are involved with disease
  • No clinical evidence of pulmonary insufficiency unless the lungs are involved with disease
  • AST and ALT < 3 times upper limit of normal (ULN)*
  • Bilirubin < 2.0 mg/dL*
  • Creatinine < 2 times ULN OR creatinine clearance or glomerular filtration rate > 50% of the lower limit of normal
  • LVEF > 45% OR shortening fraction > 20%
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No active infection, defined as absence of an infectious diagnosis or (in patients who have had a recent positive infectious diagnosis) the resolution of fever, documentation of negative cultures or antigen testing, continuation or completion of a course of appropriate therapy, and presence of stable to resolving clinical symptoms
  • No evidence of HIV infection OR known HIV positivity NOTE: *Does not apply if liver is involved with disease

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • No prior stem cell transplantation
  • No other concurrent immunosuppressive therapy

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Behandeling
  • Toewijzing: NVT
  • Interventioneel model: Opdracht voor een enkele groep
  • Masker: Geen (open label)

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Feasibility of making and administering the adoptive T cell product
Tijdsspanne: from conditioning through administration of anergized cells on day 35-42
ability to collect sufficient cells, make anergized product with good viability, without contamination and infuse per study toxicity of the conditioning regimen, the likelihood of engraftment, and the subsequent percentage of individuals who would be eligible to receive aDLI were determined.
from conditioning through administration of anergized cells on day 35-42
Safety of administering the adoptive T cell product on day 35-42 post haploidentical transplant
Tijdsspanne: the period from aDLI infusion through D100
rates of graft failure with CD34 selected product, adverse and severe adverse reactions attributable to infusion of anergized donor cells, including fever, hypotension, acute graft vs host disease, organ dysfunction
the period from aDLI infusion through D100
Alloreactivity engendered by administering the adoptive T cell product
Tijdsspanne: from cell infusion through day 100
occurrence and severity of acute GVHD
from cell infusion through day 100

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Efficacy in restoring adaptive immunity
Tijdsspanne: from aDLI thorough 1 year
incidence of viral infection and type of immune reconstitution by phenotype and function of T cells
from aDLI thorough 1 year

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Onderzoekers

  • Studie stoel: Eva Guinan, MD, Dana-Farber Cancer Institute

Publicaties en nuttige links

De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Werkelijk)

1 juni 2005

Primaire voltooiing (Werkelijk)

1 juni 2010

Studie voltooiing (Werkelijk)

16 mei 2018

Studieregistratiedata

Eerst ingediend

13 september 2006

Eerst ingediend dat voldeed aan de QC-criteria

13 september 2006

Eerst geplaatst (Schatting)

15 september 2006

Updates van studierecords

Laatste update geplaatst (Werkelijk)

5 juli 2019

Laatste update ingediend die voldeed aan QC-criteria

1 juli 2019

Laatst geverifieerd

1 juli 2019

Meer informatie

Termen gerelateerd aan deze studie

Andere studie-ID-nummers

  • 05-030
  • P30CA006516 (Subsidie/contract van de Amerikaanse NIH)
  • P01CA100265 (Subsidie/contract van de Amerikaanse NIH)
  • MDA-2005-0695

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

NEE

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Klinische onderzoeken op Myelodysplastische syndromen

  • The Champ Foundation
    Children's Hospital of Philadelphia; The Cleveland Clinic
    Werving
    Pearson-syndroom | Single Large Scale Mitochondrial DNA Deletion Syndromes (SLSMDS)
    Verenigde Staten

Klinische onderzoeken op methylprednisolon

3
Abonneren