Stem Cell Transplantation in Patients With High-Risk and Recurrent Pediatric Sarcomas
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|ClinicalTrials.gov Identifier: NCT00043979|
Recruitment Status : Completed
First Posted : August 16, 2002
Results First Posted : September 13, 2013
Last Update Posted : May 31, 2017
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.
|Condition or disease||Intervention/treatment||Phase|
|Sarcoma||Drug: F-18 Fluorodeoxyglucose Biological: therapeutic allogeneic lymphocytes Drug: cyclophosphamide Drug: cyclosporine Drug: doxorubicin hydrochloride Drug: etoposide Drug: fludarabine phosphate Drug: melphalan Drug: prednisone Drug: sirolimus Drug: tacrolimus Drug: vincristine sulfate Procedure: peripheral blood stem cell transplantation Drug: Filgrastim Procedure: Peripheral Blood Stem Cell donation||Phase 2|
- 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.
- 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.
- 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.
-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 (Clinical Trial)|
|Actual Enrollment :||60 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Pilot Study of Allogeneic/Syngeneic Blood Stem Cell Transplantation in Patients With High-Risk and Recurrent Pediatric Sarcomas|
|Actual Study Start Date :||September 19, 2002|
|Actual Primary Completion Date :||May 1, 2009|
|Actual Study Completion Date :||December 14, 2011|
Experimental: Arm 1- Sibling Donors
Donors (n = 30) were matched first degree relatives who were eligible to donate peripheral blood stem cells.
Procedure: Peripheral Blood Stem Cell donation
Experimental: Arm 2 - Recipients
Recipients (n=30) were enrolled to receive peripheral blood stem cells (PBSC) and receive either cyclosporine or tacrolimus and sirolimus for graft versus host disease (GVHD) prophylaxis.
Drug: F-18 Fluorodeoxyglucose
Other Name: FDG
Biological: therapeutic allogeneic lymphocytes
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.
Other Name: Cytoxan
6 mg/kg per dose orally every other day (no day 9 dose).
Other Name: Sandimmune
Drug: doxorubicin hydrochloride
Induction - 10 mg/m^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days. Days 1, 2, 3, 4.
Other Name: Adriamycin
50 mg/m^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days. Days 1, 2, 3, 4.
Other Name: Vepesid
Drug: fludarabine phosphate
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.
Other Name: Fludara
Transplant - 100 mg/m^2 per day intravenous (IV) infusion over 15 minutes for 1 day; day -2.
Other Name: Alkeran
Induction - 60 mg/m^2 per day in 2-4 divided doses by mouth daily for 5 days; days 1, 2, 3, 4, 5.
Other Name: Deltasone
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.
Other Name: Rapamune
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.
Other Name: Prograf
Drug: vincristine sulfate
Induction - 0.4 mg/m^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days; 1, 2, 3, 4.
Other Name: Oncovin
Procedure: peripheral blood stem cell transplantation
Stem cells from a healthy donor are collected and transplanted into the patient using a central venous catheter.
Other Name: PBSCT
- Number of Participants With Engraftment [ Time Frame: 100 days ]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.
- Toxicity [ Time Frame: 16.5 months ]Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
- Number of Participants With Acute and Chronic GVHD [ Time Frame: up to 5 years or death ]Acute GVHD as by Modified Glucksberg Criteria occurring before day 100. Chronic GVHD as per Seattle criteria occurring after day 100.
- Median Time to Reach Absolute Neutrophil Count of 500/mm(3) [ Time Frame: up to 12 days ]Days for participants to achieve a neutrophil count of 500/mm(3).
- Median Time to Reach a Platelet Count of 50,000/mm(3) [ Time Frame: up to 43 days ]Days for participants to achieve a platelet count of 50,000/mm(3).
- Early Post Transplantation Relapse [ Time Frame: up to 300 days ]Participants who experienced recurrence or progression of disease following transplant.
- Median Progression Free Survival [ Time Frame: up to 77 months ]Progression free survival was based on the time from on-study date until progression or last follow-up.
- Two Year Survival Rate for Patients Undergoing Allo-Hematopoietic Stem Cell Transplant [ Time Frame: 2 years ]Participants who are alive at two years following Allo-Hematopoietic Stem Cell Transplant.
- Number of Participants to Complete Conversion to >95% Donor Chimerism [ Time Frame: up to 30 days ]Participants who tolerated the transplantation regimen and accepted >95% of the donors blood, marrow, and/or tissue.
- Cluster of Differentiation 4 (CD4) Reconstitution [ Time Frame: Day +28-42 ]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.
- Best Response Post-Hematopoietic Stem Cell Transplant EOCH (Etoposide, Vincristine, Cyclophosphamide, and Doxorubicin) [ Time Frame: up to 10 cycles of therapy or 280 days ]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.
- Median Survival From Date of Progression [ Time Frame: up to 77 months ]Median survival from date of progression is based on the time from on-study date until progression or last follow-up.
- Number of Participants Who Experienced Graft Versus Tumor Effect (GVT) [ Time Frame: up to day 100 ]GVT is defined as tumor response after day 42 post-transplantation without cytotoxic therapy.
- Post-Hematopoietic Stem Cell Transplant (HSCT) Radiotherapy [ Time Frame: up to 6 cycles or 168 days ]Site of radiotherapy (high energy radiation) and/or toxicity experienced by the participants post HSCT radiotherapy. Grading was preformed using the Modified Glucksberg Criteria.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00043979
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Terry Fry, M.D.||National Cancer Institute (NCI)|