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Phase I Pilot Study of Sequential High-Dose Chemotherapy for Stage IV Breast Cancer: Methotrexate/Fluorouracil/Leucovorin, Cyclophosphamide, Thiotepa with Peripheral Blood Stem Cell Rescue (with MDR1 and NeoR Gene Transduction of Cells), Paclitaxel, and Doxorubicin (Summary Last Modified 08/2000)
Alternate Title High-Dose Chemotherapy, Peripheral Stem Cell Transplantation, and Gene Therapy in Treating Women With Stage IV Breast Cancer
Objectives I. Evaluate the feasibility of retroviral transfer of the multidrug resistance (MDR1) and neomycin resistance (NeoR) genes into peripheral blood progenitor cells and the reconstitution of gene-marked cells following nonablative chemotherapy in the initial treatment of patients with metastatic breast cancer. II. Determine whether the transduced MDR1 gene affects in vivo expansion of MDR1-transduced cells relative to NeoR cells after treatment with the noncross-resistant drugs paclitaxel (TAX) and doxorubicin (DOX). III. Evaluate the feasibility of sequential administration of 4 courses of antimetabolite chemotherapy (methotrexate/fluorouracil) followed by 3 courses of high-dose single-agent alkylator chemotherapy (cyclophosphamide and thiotepa) followed by multiple courses of TAX and DOX in these patients. IV. Assess the toxicity of this regimen, and determine whether evidence of in vivo expansion of MDR1-transduced cells can be correlated with decreased myelotoxicity. V. Study the pattern of T-cell depletion and recovery and T-cell signal transduction and function following dose-intensive chemotherapy. Entry Criteria Disease Characteristics: Histologically diagnosed stage IV breast cancer No CNS metastases (CT or MRI required) Hormone receptor status: Not specified Prior/Concurrent Therapy: Biologic therapy: Not specified Chemotherapy: No prior chemotherapy for metastatic disease Prior adjuvant chemotherapy allowed At least 3 weeks since chemotherapy and recovered Endocrine therapy: No chronic steroids Radiotherapy: At least 3 weeks since radiotherapy and recovered No more than 25% of bone marrow previously irradiated Surgery: Not specified Patient Characteristics: Age: 18 and over Sex: Female Menopausal status: Any status Performance status: ECOG 0-2 Hematopoietic: (in absence of bone marrow metastases) Absolute neutrophil count greater than 1,200/mm3 Platelet count greater than 100,000/mm3 Hepatic: (in absence of liver metastases) Bilirubin less than 1.8 mg/dL Transaminases less than 2 times normal Renal: (unless due to metastases) Creatinine less than 2.0 mg/dL Creatinine clearance (12 to 24-hour) greater than 50 mL/min Cardiovascular: Left ventricular ejection fraction at least 40% on MUGA OR Left ventricular function normal on echocardiogram No clinically significant cardiovascular disease, e.g.: Arrhythmia Congestive heart failure Coronary artery disease Other: No HIV antibody or hepatitis B antibody/antigen No requirement for anticoagulants No nonmalignant medical or psychiatric condition that precludes entry No second malignancy within 10 years except: In situ cervical cancer Basal cell carcinoma Prior breast cancer Not pregnant or nursing Expected Enrollment A maximum of 25 patients will be treated. Outline Patients with undrainable pleural effusions or ascites proceed directly to consolidation therapy. Other patients receive induction chemotherapy with methotrexate, fluorouracil, and leucovorin every 2 weeks for 2-4 courses. Patients then receive one 3-week course of consolidation therapy with cyclophosphamide followed by daily filgrastim (granulocyte colony-stimulating factor; G-CSF) and leukapheresis. Of the cells collected, one half are transduced with the multidrug resistance gene, and one half with the neomycin resistance gene. Patients receive myeloablative doses of thiotepa followed by G-CSF and stem cells transduced with the multidrug resistance and neomycin resistance genes. Patients who did not have the minimum number of peripheral cells collected do not receive thiotepa. After hematopoietic reconstitution, patients receive 24-hour infusions of paclitaxel every 3 weeks for four doses, followed by doxorubicin or vinblastine every 3 weeks for 4 doses. Patients are followed monthly for 3 months, then q 3 months for 9 months and every 6 months thereafter. Trial Lead Organizations NCI - Center for Cancer Research
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol. |
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