Allogeneic Natural Killer (NK) Cells in Patients With Advanced Metastatic Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy before a donor natural killer (NK) cell infusion helps stop the growth of tumor cells. It also helps stop the patient's immune system from rejecting the donor's cells. Giving NK cells from a related donor may kill the tumor cells. PURPOSE: This study furthers the research of previous studies (MT2003-01 and MT2004-25) which were to determine a specific preparatory regimen (cyclophosphamide and fludarabine) could create an environment in which infused NK cells can grow and effectively treat patients with relapsed AML. This study will test the previous regimen in patients with breast cancer.

Detailed Description
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We believe that administration of related allogeneic (donor) natural killer cells along with IL-2, rather than autologous natural killer cells will provide the most effective anticancer therapy in this setting, and wish to test this approach. To do this, we will select a related donor who is partially HLA-matched with the study subject, to increase the likelihood that donor natural killer cells will kill the subject's cancer cells. We will also give chemotherapy drugs to increase the subject's tolerance for the donor natural killer cells. We will test the use of donor natural killer (NK) cell infusions. The immune system has a special way that it sees and identifies cancer cells or foreign agents (like viruses). The subject's own NK cells may not attack their cancer because NK cells see the tumor cells as self (a coating on the cell surface identifies a cell as self or non-self). We have reason to believe that NK cells may not kill cancer cells because NK cells have special receptors that turn them off when they encounter cancer cells (by seeing them as self). We may be able to get around this problem by using donor NK cells. Finally, subjects will receive a dose of subcutaneous IL-2 3 times a week (for 2 weeks) which has been proven safe in our previous studies to stimulate the natural killer cells.

Official Title
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Allogeneic Natural Killer Cells in Patients With Advanced Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Cyclophosphamide
* Radiation: Total body irradiation
* Other: Natural killer cell infusion
* Biological: Interleukin-2


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of metastatic breast cancer that has progressed on or failed at least one salvage chemotherapy regimen for metastatic disease and that meets the following disease specific related criteria: Measureable metastatic disease per Response Evaluation Criteria In Solid Tumor (RECIST) - bone only not eligible. Disease progression while receiving prior therapy with a hormonal agent (if estrogen/progesterone receptor-positive) and/or trastuzumab (Herceptin®) (if HER2-neu positive) Brain metastases allowed provided they are stable for ≥ 3 months after prior treatment Related HLA-haploidentical natural killer cell donor available (by ≥ class I serologic typing) Male or female Performance status 50-100% Platelet count ≥ 80,000/mm³ (unsupported by transfusions) Hemoglobin ≥ 9 g/dL (unsupported by transfusions) Absolute neutrophil count ≥ 1,000/mm³ (unsupported by sargramostim [GM-CSF] or filgrastim [G-CSF]) Creatinine ≤ 2.0 mg/dL Liver function tests < 5 times normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception LVEF > 40%* Pulmonary function > 50%* (DLCO corrected AND FEV_1) No active infection (i.e., afebrile, off antibiotics, and no uninvestigated radiologic lesions) Exclusion Criteria: At least 3 days since prior prednisone or other immunosuppressive medications No other concurrent therapy for cancer

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All Treated Patients<br>All patients with advanced metastatic breast cancer treated with natural killer cells after receiving fludarabine, cyclosphosphamide and total body irradiation. | Drug: Fludarabine<br>* administered intravenously 25 mg/m^2 times 5 doses<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* administered intravenously 60 mg/kg days times 2 doses.<br>* Other names: Endoxan, Cytoxan, Neosar, Procytox;Radiation: Total body irradiation<br>* 200 cGy (gray) on day -1<br>* Other names: radiation;Other: Natural killer cell infusion<br>* Infused cell dose is within the range of 1.5-8.0 x 10^7/kg. Cell counts are based on total cells infused after the activation culture and washing determined on the morning of infusion.<br>* Other names: NK cells;Biological: Interleukin-2<br>* administered subcutaneously (10 MU) 3 times per week for 6 doses<br>* Other names: IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Had Expansion of Natural Killer Cells | Successful Natural Killer (NK) cell expansion is defined as detection of an absolute circulating donor-derived NK cell count of >100 cells/ul of whole blood 14 days after infusion with <5% donor T and B cells in mononuclear population (in metastatic breast cancer patients). | Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients by Disease Response | Defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria: Complete Response (CR: Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions of appearance of one or more new lesions of clinical benefit (CB; stable disease for greater than 6 months. | 6 Months, 1 Year | 
| Number of Patients Who Died While on Study | Number of patients who died within 100 days and after 100 days of natural killer (NK) treatment with or without total body irradiation. | Within 100 days, After 100 days | 
| Overall Median Number of Days Patients Alive After Treatment | Calculated median number of days of survival (patients alive days after treatment). | First Day of Treatment Until Death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, male breast cancer, recurrent breast cancer