Stem Cell Transplant With Th2/Tc2 Cells to Treat Advanced Breast Cancer
This Phase 1 trial will investigate the safety of a modified stem cell transplant procedure for treating advanced breast cancer. Patients with cancers can sometimes benefit greatly from transplants of stem cells (cells produced by the bone marrow that mature into blood cells). In addition to producing new bone marrow and restoring normal blood production and immunity, the donated cells fight any residual tumor cells that might have remained in the body, in what is called a "graft-versus-tumor" effect. However, severe problems, or sometimes even death, may follow these transplants as a result of the high-dose chemotherapy and radiation that accompany the procedure. Also, donated immune cells called lymphocytes, or T cells, sometimes attack healthy tissues in a reaction called graft-versus-host-disease (GVHD), damaging organs such as the liver, intestines and skin. This study will use the following strategies to try to reduce these risks:
- "Induction chemotherapy" to reduce patients' immunity in an attempt to prevent rejection of the donated stem cells
- Reduced-intensity conditioning chemotherapy that is easier for the body to tolerate and involves a shorter period of complete immune suppression
- Removal of lymphocytes from the donor stem cells for transfusion in small quantities at monthly intervals following the stem cell transplant to reduce the risk of GVHD
- Transplant of specific lymphocytes called Th2/Tc2 cells that may increase the percentage of donor stem cells accepted by the patient without significantly increasing GVHD
Patients between 18 and 75 years of age with advanced (stage IV) breast cancer that does not respond to standard therapy may be eligible for this study. Candidates are screened with a medical history, physical and dental examinations, x-ray studies and bone marrow biopsies to evaluate disease status, blood and urine tests (including a blood test for genetic match with the donor), and lung and heart function tests.
Participants have a central venous line (large plastic tube) placed into a major vein. This tube stays in the body during the entire treatment period for infusing the donated stem cells and T lymphocytes, giving medications, including chemotherapy and other drugs, antibiotics, and blood transfusions, and withdrawing blood samples. Treatment starts with induction chemotherapy, in which patients receive one or two cycles of the anti-cancer drugs fludarabine and cyclophosphamide. (One cycle consists of 4 days on drug therapy followed by a 17-day rest period.) G-CSF, a drug that boosts white cell production, is also given to reduce the risk of infection. Several days before the transplant procedure, patients begin conditioning chemotherapy with higher doses of cyclophosphamide and fludarabine. Three days after the conditioning therapy is completed, the stem cells are infused. To help prevent both rejection of the donor stem cells and GVHD, patients receive cyclosporine (first by vein and later by mouth) for several weeks after the transplant. Infusions of donor lymphocytes begin about 6 weeks after the transplant to boost the immune system and enhance the graft-versus-tumor effect.
Patients may leave the hospital when they are able to eat and drink, have no fever or infection, and have a normal or near-normal white cell count. They return for follow-up visits twice a week for the first 100 days after the transplant, then every 3 months, then 6 months and then yearly for at least 5 years post-transplant. The visits include a medical history, physical examination, and blood draws, as well as disease staging with CT scans every month for the first 6 months.
|Study Design:||Primary Purpose: Treatment|
|Official Title:||Allogeneic Breast Protocol 2: Phase I Trial of T Cell Exchange With Th2/Tc2 Cells for Allogeneic Stem Cell Transplantation After Reduced Intensity Conditioning for Metastatic Breast Cancer|
- To determine the safety as defined by the incidence of acute graft-versus-host disease and feasibility of administering in vitro generated donor T cells of Th2/Tc2 phenotype to augment a T cell depleted allograft after reduced-intensity conditio...
- To determine if the transplantation of a T cell depleted allograft augmented with Th2/Tc2 ell can result in a state of rapid complete donor chimerism after reduced-intensity conditioning regimen.
|Study Start Date:||March 5, 2004|
|Study Completion Date:||August 9, 2013|
|Primary Completion Date:||August 9, 2013 (Final data collection date for primary outcome measure)|
- In CC# 00-C-0119 we were able to demonstrate that allogeneic T cells could mediate a clinically relevant graft-versus-tumor (GVT) effect against MBC after a reduced-intensity, T cell depleted allogeneic hematopoietic stem cell transplant (alloHSCT).
- Responses were observed after establishment of complete lymphoid chimerism, which was frequently delayed and required the use of planned donor lymphocyte infusions (DLI). DLI were associated with a significant incidence of graft-versus-host disease (GVHD).
- In murine models, in vitro generated T cells of Th2/Tc2 phenotype can facilitate engraftment of HLA disparate allografts with significantly reduced GVHD as compared to T cell replete allografts that have not been manipulated. In addition, Th2/Tc2 cells provide an anti-tumor effect through the perforin/granzyme pathway.
- Allogeneic Th2/Tc2 cells may facilitate rapid allo-engraftment post-transplant with reduced GVHD. In addition, the perforin-mediated anti-tumor activity of Th2/Tc2 cells should provide earlier benefit compared with T-cell depleted allografts.
-To determine the safety, as defined by the incidence of acute graft-versus-host disease, and feasibility of administering in vitro generated donor T cells of Th2/Tc2 phenotype to augment a T cell depleted allograft (T cell exchange) after reduced-intensity conditioning.
- Patients with measurable, metastatic breast cancer and an HLA matched sibling donor
- Patients must have received treatment with a taxane, an anthracycline, a hormonal agent and/or Herceptin, if the tumor expresses the respective receptors, and at least one treatment for metastatic disease that has not resulted in a complete response.
- Donors will initially have lymphocytes collected to generate the Th2/Tc2 product and then have blood stem cells collected following mobilization with filgrastim. The stem cell product will be T-cell depleted, and the T-cell dose will be adjusted to 1 x 10(5) CD3+ cells/kg.
- Patients will receive induction (immune depleting) chemotherapy with the goal of reducing circulating CD4+ cell less than 50/microliter prior to proceeding to alloHSCT.
- Patients will receive a reduced-intensity conditioning regimen consisting of fludarabine and cyclophosphamide. This will be followed by infusion of the T cell depleted allograft, which will be supplemented with Th2/Tc2 cells (i.e. T cell exchange).
- Cyclosporine will be discontinued after 40 days to permit a full GVT effect. Patients may receive donor lymphocyte infusions at days +42, +70, +98 post-transplant to further potentiate a GVT effect.
- Patients will be enrolled in three cohorts, with escalating Th2/Tc2 cell doses (0.5 - 12.5 x 10(7) cells/kg) given in a phase-I manner.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00079625
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Daniel H Fowler, M.D.||National Cancer Institute (NCI)|