Stem Cell Transplantation in Patients With High-Risk and Recurrent Pediatric Sarcomas

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Pilot Study of Allogeneic/Syngeneic Blood Stem Cell Transplantation in Patients With High-Risk and Recurrent Pediatric Sarcomas

Conditions
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Sarcoma

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: PATIENT The following diagnoses will be considered: Patients with Ewing's sarcoma family of tumors, or alveolar rhabdomyosarcoma in one of the following categories: Patients who present at the time of initial diagnosis with bone or bone marrow metastases may be enrolled after completion of standard front-line therapy. Standard front line therapy for alveolar rhabdomyosarcoma should include vincristine and cyclophosphamide, plus actinomycin D and/or adriamycin. For patients with Ewing's sarcoma, standard front line therapy should include vincristine, cyclophosphamide, adriamycin, ifosfamide and etoposide. Patients with recurrence of tumor at any site less than one year after completing standard front-line therapy or with a second or subsequent recurrence at any time after completing standard front-line therapy. Patients with progression or persistence of disease while receiving standard front-line chemotherapy who cannot achieve a complete response (CR) with local treatment modalities. The following patients with desmoplastic small round cell tumor are eligible after receiving front line standard therapy, which is defined as a regimen containing at least vincristine, cyclophosphamide, and adriamycin: unresectable disease metastatic tumor (abdominal and extra-abdominal disease) progressive or persistent while receiving standard therapy recurrence within one year of completing therapy Patients without evaluable tumor at the time of enrollment are eligible Patients who have previously received high-dose chemotherapy with autologous stem cell rescue are eligible for this trial. Patient age 5-35 at enrollment. Availability of a 5 or 6 antigen human leukocyte antigen (HLA)-matched first-degree relative donor (single HLA-A or B mismatch allowed). Genotypically identical twins may serve as stem cell donors. Genotypic identity must be confirmed by restrictive fragment length polymorphism (RFLP) analysis. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 or, for children less than or equal 10 years of age, Lansky greater than or equal 60 Cardiac function: Left ventricular ejection fraction greater than or equal to 45% by multi-gated acquisition scan (MUGA), fractional shortening greater than or equal 28% by echocardiogram (ECHO) or left ventricular ejection fraction greater than or equal 55% by ECHO. Pulmonary function: carbon monoxide diffusing capacity (DLCO) greater than or equal to 50% of the expected value corrected for alveolar volume. Renal function: Age-adjusted normal serum creatinine according to the following table or a creatinine clearance greater than or equal to 60 ml/min/1.73 m^2. Age (years) Maximum serum creatinine (mg/dl) less than or equal to 5 0.8 greater than 5, less than or equal to 10 1.0 greater than 10, less than or equal to15 1.2, greater than 15 1.5 Liver function: Serum total bilirubin less than 2 mg/dl, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 times upper limit of normal. Marrow function: absolute neutrophil count (ANC) must be greater than 750/mm^3 (unless due to underlying disease in which case there is no grade restriction), platelet count must be greater than or equal to 75,000/mm^3 (not achieved by transfusion) unless due to underlying disease in which case there is no grade restriction). Lymphopenia, cluster of differentiation 4 (CD4) lymphopenia, leukopenia, and anemia will not render patients ineligible. Ability to give informed consent. For patients less than18 years of age their legal guardian must give informed consent. Pediatric patients will be included in age appropriate discussion in order to obtain verbal assent. Durable power of attorney form completed (patients greater than or equal to18 years of age only). INCLUSION CRITERIA: DONOR Weight greater than or equal 15 kilograms. First degree relative with genotypic identity at 5 or 6 HLA loci (single HLAA or B locus mismatch allowed). Genotypically identical twins may serve as stem cell donors. Genotypic identity must be confirmed by RFLP analysis. For donors less than 18 years of age, he/she must be the oldest suitable donor, their legal guardian must give informed consent, the donor must give verbal assent, and he/she must be cleared by social work and a mental health specialist to participate. For donors greater than or equal to 18 years of age, ability to give informed consent. Adequate peripheral venous access for apheresis or consent to use a temporary central venous catheter for apheresis. Donor selection criteria will be in accordance with National Institutes of Health (NIH)/Clinical Center (CC) Department of Transfusion Medicine Standards. EXCLUSION CRITERIA: PATIENT Uncontrolled fungal infection. History of untreated CNS tumor involvement. Extradural masses which have not invaded the brain parenchyma (as is commonly observed in Ewing's sarcoma family of tumors) or parameningeal tumors (as is commonly observed in rhabdomyosarcoma) without evidence for leptomeningeal spread will not render the patient ineligible. Patients with previous central nervous system (CNS) tumor involvement that has been treated and has been stable for at least 6 weeks are eligible. Lactating or pregnant females. Human immunodeficiency virus (HIV) positive (due to unacceptable risk following allogeneic transplantation). Hepatitis B surface antigen (HBsAg) positive or hepatitis C antibody positive with elevated liver transaminases. All patients with chronic active hepatitis (including those on treatment) are ineligible. High risk of inability to comply with transplant protocol, or inability to give appropriate informed consent in the estimation of the principal investigator (PI), social work, or the stem cell transplant team. Fanconi Anemia EXCLUSION CRITERIA: DONOR History of medical illness which poses a risk to donation in the estimation of the PI or the Department of Transfusion Medicine physician including, but not limited to stroke, hypertension that is not controlled with medication, or heart disease. Individuals with symptomatic angina or a history of coronary bypass grafting or angioplasty will not be eligible. History of congenital hematologic, immunologic, oncologic or metabolic disorder, which poses a prohibitive risk to the recipient in the estimation of the PI. Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000/micro l). Lactating or pregnant females. Donors of childbearing potential must use an effective method of contraception during the time they are receiving growth colony stimulating factor (G-CSF). The effects of cytokine administration on a fetus are unknown and may be potentially harmful. The effects upon breast milk are also unknown and may potentially be harmful to the infant. Human immunodeficiency virus (HIV)-positive, hepatitis B surface antigen (HBsAg) positive or hepatitis C antibody positive. Donors are providing an allogeneic blood product and there is the potential risk of transmitting these viral illnesses to the recipient. High risk of inability to comply with transplant protocol.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 35 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1- Sibling Donors<br>Donors (n = 30) were matched first degree relatives who were eligible to donate peripheral blood stem cells. | Drug: Filgrastim<br> <br> Procedure: Peripheral Blood Stem Cell donation<br> <br> |
| Experimental: Arm 2 - Recipients<br>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<br> <br> * Other names: FDG;Biological: therapeutic allogeneic lymphocytes<br>* Lymphocyte cells are collected from a healthy donor by apheresis and infused into the patient with a central venous catheter.<br>Drug: cyclophosphamide<br>* 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.<br>* Other names: Cytoxan;Drug: cyclosporine<br>* 6 mg/kg per dose orally every other day (no day 9 dose).<br>* Other names: Sandimmune;Drug: doxorubicin hydrochloride<br>* Induction - 10 mg/m^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days. Days 1, 2, 3, 4.<br>* Other names: Adriamycin;Drug: etoposide<br>* 50 mg/m^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days. Days 1, 2, 3, 4.<br>* Other names: Vepesid;Drug: fludarabine phosphate<br>* 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.<br>* Other names: Fludara;Drug: melphalan<br>* Transplant - 100 mg/m^2 per day intravenous (IV) infusion over 15 minutes for 1 day; day -2.<br>* Other names: Alkeran;Drug: prednisone<br>* Induction - 60 mg/m^2 per day in 2-4 divided doses by mouth daily for 5 days; days 1, 2, 3, 4, 5.<br>* Other names: Deltasone;Drug: sirolimus<br>* 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.<br>* Other names: Rapamune;Drug: tacrolimus<br>* 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.<br>* Other names: Prograf;Drug: vincristine sulfate<br>* Induction - 0.4 mg/m^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days; 1, 2, 3, 4.<br>* Other names: Oncovin;Procedure: peripheral blood stem cell transplantation<br>* Stem cells from a healthy donor are collected and transplanted into the patient using a central venous catheter.<br>* Other names: PBSCT;Drug: Filgrastim<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 100 days | 
| Toxicity | Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module. | 16.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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). | 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). | up to 43 days | 
| Early Post Transplantation Relapse | Participants who experienced recurrence or progression of disease following transplant. | 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. | 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. | 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. | 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. | 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. | 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. | up to 77 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ewing's Sarcoma, Rhabdomyosarcoma, Desmoplastic Small Round Cell Tumor, Sarcoma, Ewing Sarcoma