This study will examine the safety and effectiveness of allogeneic (donor) bone marrow transplant in treating metastatic breast cancer (breast cancer that has spread to other places in the body, such as the lymph nodes, lungs, liver, or bones.

Patients with metastatic breast cancer age 18 to 75 will be tested for matching with a donor (family member). Both donor and patient will have a medical history, physical examination and blood tests to determine eligibility for the study.

Patients enrolled in the study will have further tests, including CT and MRI scans, bone marrow aspiration, and possibly a tumor needle biopsy before beginning treatment. A central venous catheter (a flexible plastic tube) inserted into a vein will remain in place for the treatment period and will be used to deliver chemotherapy and medications, infuse donor stem cells and white blood cells, transfuse red blood cells or platelets.

Both patient and donor will receive injections of a hormone called G-CSF for 5 to 7 days before the each donate stem cells. G-CSF increases the number of stem cells released from the marrow into the blood, increasing the amount of cells that can be collected.

Patients will receive the drugs fludarabine and cyclophosphamide for 4 days to shrink or stabilize the growth of the breast tumor and to weaken the immune system so that it does not reject and destroy the donated stem cells. Depending on the response of both the tumor and the immune system, the transplant may follow the one dose, or a second dose may be given after a rest period. Additional G-CSF will be given after chemotherapy to increase the white cell count, thereby reducing the risk of infection.

The initial chemotherapy will be followed by 4 consecutive days of "conditioning chemotherapy" of higher doses of fludarabine and cyclophosphamide, beginning 6 days before the transplant. Cyclosporine will be given both before and after the stem cells are infused through the central line to prevent the patient's immune system from rejecting the donated cells and to prevent the donated immune cells from attacking the patient's tissues. The drug will be reduced over several weeks in patients whose tissues are not being damaged by the donor cells.

After discharge from the hospital, patients will continue to take antifungal, antiviral and antibiotic medicines at home. They may receive one or more "booster" infusions of donated white cells at set times to enhance the tumor-killing effect.

Patients will be followed twice weekly for the first 100 days after the transplant with a history, physical examination, and blood tests. After that, visits will be scheduled every 3 months, then every 6 months, and then yearly during the minimum 5 years of follow-up. CT scans will be done every month for the first 6 months.

Condition	Treatment or Intervention	Phase
Breast Cancer Breast Neoplasm	Drug: Cyclophosphamide; Fludarabine; Cyclosporine; Mesna, G-CSF; MABs  Drug: 3A1  Drug: 95-5-49  Drug: 96-6-42  Device: Baxter Isolex 300i Stem Cell Collection System	Phase I

Despite being relatively responsive to available therapies, the prognosis for metastatic breast cancer patients is poor with a median survival of less than two years. These results point to the need for new approaches for the treatment of metastatic breast cancer. Allogeneic stem cell transplantation (alloSCT) has been successful in the treatment of hematologic diseases. The therapeutic effect of alloSCT in this clinical setting is mediated in part by T cells in the allograft, which is described as the "graft-versus-tumor" (GVT) effect. The GVT effect is supported by observations that donor lymphocytes infusions (DLI) are effective for patients relapsing after alloSCT. It is unknown whether a GVT effect has relevant clinical implications in breast cancer patients, but there is anecdotal evidence to support this possibility. There is significant concern over subjecting patients to the potential morbidity and mortality associated with alloSCT (e.g. graft-versus-host, GVHD). It is the intent of this study to reduce the risk of potential complications associated with alloSCT and to evaluate whether a GVT effect occurs in breast cancer. The specific objectives of this protocol are: 1) to determine if the transplantation of a T cell depleted allograft in the setting of an immunoablative conditioning regiment can result in a state of mixed host/donor chimerism, and 2) to determine if an allogeneic GVT response occurs in metastatic breast cancer.

Patients eligible for this protocol must have measurable, metastatic disease, and an HLA matched sibling donor. Patients' disease must have progressed after treatment with a taxane and an anthracycline, as well as a hormonal agent and/or Herceptin, if their tumor expressed estrogen/progesterone receptors or Her-2-neu, respectively. Patients will receive one to two cycles of immune depleting chemotherapy, prior to proceeding to transplant, with the goal of reducing the CD4+ count to less than 50. Donors will have their blood collected following mobilization with filgrastim. The collected blood stem cells will be T cell depleted, and the T cell dose will be adjusted to 1 x 10(5) CD3+ cell/kg. T cells will also be simultaneously collected and stored for planned delayed, dose-escalated DLI post-transplant. Patients will receive a non-myeloablative conditioning regimen consisting of fludarabine and cyclophosphamide. This will be followed by infusion of the T cell depleted allograft. Cyclosporine will be administered for 42 days to prevent GVHD and then discontinued to permit a full GVT effect. The initial DLI will be delayed until 42 days after transplantation to decrease the incidence of GVHD and also to permit adequate time to separate the potentially cytoreductive effects of the conditioning regimen from the GVT effects of the DLI. The patient will subsequently receive additional DLI at days +70 and +98 post-transplant with increased doses of lymphocytes if no response or GVHD is observed.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
RECIPIENT:
Patients with measurable stage IV breast cancer.
Patients must have progressed on at least one prior chemotherapy regimen in the metastatic setting. Progression is defined as an increase in disease mass or response less than partial response.
a. Patients must have received and progressed on prior therapy with a taxane and an anthracycline;
b. Patients whose tumor express estrogen/progesterone receptors must have received and progressed on at least one hormonal agent;
c. Patients whose tumor expressed Her2-neu must have received and progressed on Herceptin;
d. Patients who have progressed after or did not achieve a complete response after an autologous stem cell transplantation are eligible for this protocol. Patients must recovered normal hematologic recovery after transplant.
e. Patients who have received the above mentioned agents in the adjuvant setting and subsequently relapsed are considered eligible for this protocol.
Patients 18-70 years of age.
Karnofsky performance greater than or equal to 80%.
Life expectancy greater than 6 months.
Left ventricular ejection fraction has to be greater than 45% by either MUGA or 2-D echo.
DLCO greater than or equal to 50% of the expected value when corrected for Hb.
Creatinine less than or equal to 1.5 mg/dl and a creatinine clearance greater than or equal to 50 ml/min.
Direct bilirubin less than or equal to 2 mg/dl, SGOT less than 4 times top normal.
Patients must be HIV negative, HBsAg negative, and Hepatitis C antibody negative.
Not pregnant or lactating. Patients of childbearing potential must use an effective method of contraception.
Consenting first-degree relative matched at 6/6 or 5/6 HLA antigens, this may include a mismatch at the D locus.
Provision for a Durable Power of Attorney.
Ability to give informed consent.
DONOR:
Age 18-75 years.
No physical contraindications to stem cell donation (i.e. severe atherosclerosis, auto-immune disease, cerebrovascular accident, prior malignancy). Patients with severe atherosclerosis by history will receive a cardiology consult and be judged eligible on a case by case basis. The exclusion of patients with a prior malignancy will be evaluated on a case by case basis. If it is felt by the investigators that the risk of potential transfer of malignant cells is far outweighed by the potential benefit of the procedure, the patient may be eligible to serve as a donor.
Donors must be HIV-negative, HBsAg negative, and Hepatitis C antibody negative.
Not pregnant or lactating. Donors of childbearing potential must use an effective method of contraception during the time they are receiving cytokines.
Ability to give informed consent.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States

Study ID Numbers:  000119; 00-C-0119
Record last reviewed:  October 1, 2004
Last Updated:  October 1, 2004
Record first received:  April 22, 2000
ClinicalTrials.gov Identifier:  NCT00005568
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-10-29