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RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop tumor cells from dividing so they stop growing or die. Allogeneic stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy. Sometimes the transplanted cells can make an immune response against the body's normal tissues. Eliminating the T cells from the donor cells before transplanting them and giving cyclosporine may prevent this from happening. Infusing donor T cells that have been treated in the laboratory may be effective in killing metastatic tumor cells by making an immune response against the person's tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of laboratory-treated donor T cells when given after chemotherapy, reduced-intensity transplantation conditioning (chemotherapy given before the transplant in doses that will not destroy all bone marrow cells), and T cell-depleted (T cells removed) donor stem cell transplantation in treating patients with metastatic breast cancer.
- Determine the safety, in terms of the incidence of acute graft-versus-host disease, and feasibility of using in vitro-generated donor T cells of Th2/Tc2 phenotype to augment a T-cell-depleted allogeneic stem cell transplantation after immunoablative induction chemotherapy and reduced-intensity transplantation conditioning in patients with metastatic breast cancer.
- Determine the effect of this treatment regimen on donor chimerism in these patients.
- Determine the effect of this treatment regimen on clinical response in these patients.
- Determine the progression-free and overall survival of patients treated with this regimen.
OUTLINE: This is a dose-escalation study of Th2/Tc2 cells.
- Immunoablative induction chemotherapy: Patients receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days 1-4. Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In order to achieve the greatest immunosuppression before transplantation, patients may receive a second course of immunoablative induction chemotherapy beginning on day 21 depending on CD4+ count.
- Transplantation preparative regimen: Beginning 7-21 days after recovery from induction chemotherapy, patients receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -6 to -3 before transplantation.
- Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours or orally every 12 hours beginning on day -1 and continuing until day 28, followed by a taper until day 40.
- Allogeneic stem cell transplantation (SCT): Patients undergo T-cell-depleted allogeneic peripheral blood SCT on day 0. Patients receive G-CSF SC beginning on day 0 and continuing until blood counts recover.
- Donor Th2/Tc2 cell administration: Patients receive donor Th2/Tc2 cells IV on day 0 after SCT. Cohorts of 6-12 patients receive escalating doses of donor Th2/Tc2 cells until feasibility is determined. Feasibility is defined as the dose level at which no more than 6 of 12 patients experience grade II-IV acute GVHD by day 42 post-transplantation.
- Donor lymphocyte infusion (DLI): Patients with progressive malignant disease and less than grade II acute GVHD at day 42 post-transplantation may receive DLI on days 42, 70, and 98.
Patients are followed every 2 weeks until approximately day 100 and then at 6, 9, 12, 18 and 24 months.
PROJECTED ACCRUAL: A total of 45 patients will be accrued for this study within 2-3 years.
Primary Purpose: Treatment
filgrastim, graft-versus-tumor induction therapy, peripheral blood lymphocyte therapy, cyclophosphamide, cyclosporine, fludarabine phosphate, peripheral blood stem cell transplantation
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
Active, not recruiting
National Cancer Institute (NCI)
Published on BioPortfolio: 2014-08-27T03:54:24-0400
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Peripheral stem cell transplantation may allow the doctor to give hi...
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The induction of prolonged survival and growth of allografts of either tumors or normal tissues which would ordinarily be rejected. It may be induced passively by introducing graft-specific antibodies from previously immunized donors, which bind to the graft's surface antigens, masking them from recognition by T-cells; or actively by prior immunization of the recipient with graft antigens which evoke specific antibodies and form antigen-antibody complexes which bind to the antigen receptor sites of the T-cells and block their cytotoxic activity.
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Immunological rejection of tumor tissue/cells following bone marrow transplantation.
Immunized T-lymphocytes which can directly destroy appropriate target cells. These cytotoxic lymphocytes may be generated in vitro in mixed lymphocyte cultures (MLC), in vivo during a graft-versus-host (GVH) reaction, or after immunization with an allograft, tumor cell or virally transformed or chemically modified target cell. The lytic phenomenon is sometimes referred to as cell-mediated lympholysis (CML). These CD8-positive cells are distinct from NATURAL KILLER CELLS and NATURAL KILLER T-CELLS. There are two effector phenotypes: TC1 and TC2.
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