This study will examine the safety and effectiveness of stem cell transplantation for treating patients with sarcomas (tumors of the bone, nerves, or soft tissue). Stem cells are immature cells in the bone marrow and blood stream that develop into blood cells. Stem cells transplanted from a healthy donor travel to the patient's bone marrow and begin producing normal cells. In patients with certain cancers, such as leukemia and lymphoma, the donor's immune cells attack the patient's cancer cells in what is called a "graft-versus-tumor" effect, contributing to cure of the disease. This study will determine whether this treatment can be used successfully to treat patients with sarcomas. Patients between 4 and 35 years of age with a sarcoma that has spread from the primary site or cannot be removed surgically, and for whom effective treatment is not available, may be eligible for this study. Candidates must have been diagnosed by the age of 30 at the time of enrollment. They must have a matched donor (usually a sibling). Participants undergo the following procedures: Donors: Stem cells are collected from the donor. To do this, the hormone granulocyte colony stimulating factor (G-CSF) is injected under the skin for several days to move stem cells out of the bone marrow into the bloodstream. Then, the cells are collected by apheresis. In this procedure the blood is drawn through a needle placed in one arm and pumped into a machine where the stem cells are separated out and removed. The rest of the blood is returned to the donor through a needle in the other arm. Patients: For patients who do not already have a central venous catheter (plastic tube), one is placed into a major vein. This tube can stay in the body the entire treatment period for giving medications, transfusing blood, , withdrawing blood samples, and delivering the donated stem cells. Before the transplant procedure, patients receive from one to three cycles of "induction" chemotherapy, with each cycle consisting of 5 days of fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone followed by at least a 17-day rest period. All the drugs are infused through the catheter except prednisone, which is taken by mouth. After the induction therapy, the patient is admitted to the hospital for 5 days of chemotherapy with high doses of cyclophosphamide, melphalan, and fludarabine. Two days later, the stem cells are infused. The anticipated hospital stay is about 3 weeks, but may be longer if complications arise. Patients are discharged when their white cell count is near normal, they have no fever or infection, they can take sufficient food and fluids by mouth, and they have no signs of serious graft-versus-host disease (GVHD)-a condition in which the donor's cells "see" the patient's cells as foreign and mount an immune response against them. After hospital discharge, patients are followed in the clinic at least once or twice weekly for a medical history, physical exam, and blood tests for 100 days. They receive medications to prevent infection and GVHD and, if needed, blood transfusions. If GVHD has not developed by about 120 days post transplant, patients receive additional white cells to boost the immune response. After 100 days, follow-up visits may be less frequent. Follow-up continues for at least 5 years. During the course of the study, patients undergo repeated medical evaluations, including blood tests and radiology studies, to check on the cancer and on any treatment side effects. On four occasions, white blood cells may be collected through apheresis to see if immune responses can be generated against the sarcomas treated in this study. Positron emission tomography (PET) scans may be done on five occasions. This test uses a radioactive material to produce images useful in detecting primary tumors and cancer that has spread.
Background: * Treatment of pediatric sarcomas has enjoyed progress in the past 25 years for patients with localized, chemosensitive disease and prognostic factors are now available to identify subsets of patients who have very dismal prognoses; patients with primary metastatic disease, especially those with bone and bone marrow metastases. * Patients with primary chemoresistant disease and early recurrence also have very poor prognoses and lack suitable treatment options. For these patients, it is critical that alternative approaches to cytotoxic chemotherapy be identified. * Basic laboratory studies have shown that Ewing's sarcoma is susceptible to immune mediated mechanisms of cytolysis in vitro. Interestingly, for Ewing's sarcoma this appears to be true for both chemosensitive and chemoresistant cell lines. * Recent progress in the field of bone marrow transplantation has identified approaches that can reproducibly induce allogeneic peripheral blood stem cell engraftment in adults with hematologic malignancies. In some cases, this same approach has shown beneficial effects for patients with solid tumors as a result of the development of allogeneic, immune-mediated graft versus tumor effects. Objectives: * To determine if the transplantation of human leukocyte antigen (HLA) matched, peripheral blood stem cells can result in full donor engraftment (greater than 95 percent by day 100) in patients with high risk-pediatric sarcomas. * To identify and characterize the toxicities of HLA-matched peripheral blood stem cell transplant (PBSCT) in patients with high-risk pediatric sarcomas. In particular we will identify the incidence of graft versus host disease (GVHD) and the pace of immune reconstitution in this population. * To determine if allogeneic graft-versus-tumor responses following allogeneic PBSCT can induce clinically significant anti-tumor effects as measured by radiographic evidence of antitumor responses following PBSCT in patients with measurable disease and improved clinical outcome compared to historical controls in this patient population with a universally poor outcome. Eligibility: * Patients, age of greater than 4 years at enrollment to less than 30 years at diagnosis and age less than 35 at enrollment, with ultra-high risk Ewing's sarcoma family of tumors, desmoplastic small round cell tumor or alveolar rhabdomyosarcoma. * Patients must have completed standard front-line therapy and salvage therapy. * Patient must have the availability of a 5 or 6 antigen HLA-matched first-degree relative donor or a genotypically identical twin. * Patients must have adequate cardiac, pulmonary, renal, liver, and marrow function. Design: -Donor will be prepared for peripheral blood stem cell harvest with Filgrastim mobilization, 10 microg/kg per day subcutaneous (SQ) for 5-7 days until they have stem cell collected by apheresis. The stem cells will then be cryopreserved. Patients will receive 1 to 3 21 day cycles of Fludarabine-EPOCH induction chemotherapy. The preparative regimen will consist of cyclophosphamide, fludarabine and melphalan followed by stem cell infusion. GVHD prophylaxis will consist of sirolimus and tacrolimus.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Lymphocyte cells are collected from a healthy donor by apheresis and infused into the patient with a central venous catheter.
Induction - 750 mg/m\^2 intravenous (IV) infusion over 30 minutes x 1 dose. Day 5. Transplant - 1200 mg/m\^2 per day IV infusion over 2 hours daily for 4 days; days -6, -5, -4, -3.
6 mg/kg per dose orally every other day (no day 9 dose).
Induction - 10 mg/m\^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days. Days 1, 2, 3, 4.
50 mg/m\^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days. Days 1, 2, 3, 4.
Induction - 25 mg/m\^2 per day intravenous (IV) infusion over 30 minutes daily for 3 days. Days 1, 2, 3. Transplant - 30 mg/m\^2 per day IV infusion over 30 minutes daily for 4 days; days -6, -5, -4, -3.
Transplant - 100 mg/m\^2 per day intravenous (IV) infusion over 15 minutes for 1 day; day -2.
Induction - 60 mg/m\^2 per day in 2-4 divided doses by mouth daily for 5 days; days 1, 2, 3, 4, 5.
Initiated on day +3. Patients \>40kg, the initial dose will be 2 mg every 24 hours orally. Patients \<40 kg, the initial dose will be 1 mg/m\^2.
Day -1 at least 24 hours before the stem cell infusion at a dose of 0.03 mg/kg/day as a continuous infusion. Twelve hours later oral dose initiated at a dose of 0.1-0.15 mg/kg/day in two divided doses every 12 hours.
Induction - 0.4 mg/m\^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days; 1, 2, 3, 4.
Stem cells from a healthy donor are collected and transplanted into the patient using a central venous catheter.
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
Number of Participants With Engraftment
Engraftment is defined as rapid conversion to complete donor chimerism and is assessed by blood counts and chimerism, \>95% donor engraftment at day 100 in \>75% of patients.
Time frame: 100 days
Toxicity
Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
Time frame: 16.5 months
Number of Participants With Acute and Chronic GVHD
Acute GVHD as by Modified Glucksberg Criteria occurring before day 100. Chronic GVHD as per Seattle criteria occurring after day 100.
Time frame: up to 5 years or death
Median Time to Reach Absolute Neutrophil Count of 500/mm(3)
Days for participants to achieve a neutrophil count of 500/mm(3).
Time frame: up to 12 days
Median Time to Reach a Platelet Count of 50,000/mm(3)
Days for participants to achieve a platelet count of 50,000/mm(3).
Time frame: up to 43 days
Early Post Transplantation Relapse
Participants who experienced recurrence or progression of disease following transplant.
Time frame: up to 300 days
Median Progression Free Survival
Progression free survival was based on the time from on-study date until progression or last follow-up.
Time frame: up to 77 months
Two Year Survival Rate for Patients Undergoing Allo-Hematopoietic Stem Cell Transplant
Participants who are alive at two years following Allo-Hematopoietic Stem Cell Transplant.
Time frame: 2 years
Number of Participants to Complete Conversion to >95% Donor Chimerism
Participants who tolerated the transplantation regimen and accepted \>95% of the donors blood, marrow, and/or tissue.
Time frame: up to 30 days
Cluster of Differentiation 4 (CD4) Reconstitution
The median CD4 count with a range of 85-1565 (absolute count) was used to determine recovery and were considered recovered if in this range. The CD4 count was established by flow cytometry testing.
Time frame: Day +28-42
Best Response Post-Hematopoietic Stem Cell Transplant EOCH (Etoposide, Vincristine, Cyclophosphamide, and Doxorubicin)
Response is defined by the Response Evaluation Criteria in Solid Tumors (RECIST). RECIST criteria offer a simplified, conservative, extraction of imaging data for wide application in clinical trials. They presume that linear measures are an adequate substitute for 2-D (dimensional) methods and registers four response categories: Complete response (CR) is disappearance of all target lesions. Partial response (PR) is 30% increase in the sum of the longest diameter of target lesions. Progressive disease (PD) is 20% increase in the sum of the longest diameter of target lesions. Stable disease (SD) is small changes that do not meet above criteria. For the purposes of this study very good partial response ((VGPR) is \>75% reduction in disease) was also employed.
Time frame: up to 10 cycles of therapy or 280 days
Median Survival From Date of Progression
Median survival from date of progression is based on the time from on-study date until progression or last follow-up.
Time frame: up to 77 months
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.