Stem Cell Transplantation in Patients With High-Risk and Recurrent Pediatric Sarcomas
Condition: Sarcoma
MeSH terms: Sarcoma
Study type: Interventional
Phase: Phase 2

Summary: 
      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: 
      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.
    

Intervention name(s): F-18 Fluorodeoxyglucose; therapeutic allogeneic lymphocytes; cyclophosphamide; cyclosporine; doxorubicin hydrochloride; etoposide; fludarabine phosphate; melphalan; prednisone; sirolimus; tacrolimus; vincristine sulfate; peripheral blood stem cell transplantation; Filgrastim; Peripheral Blood Stem Cell donation
Intervention type(s): Drug; Biological; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Procedure; Drug; Procedure
Intervention description(s): 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.
Other intervention name(s): FDG; Cytoxan; Sandimmune; Adriamycin; Vepesid; Fludara; Alkeran; Deltasone; Rapamune; Prograf; Oncovin; PBSCT
Intervention MeSH terms: Cyclosporine; Sirolimus; Prednisone; Cyclophosphamide; Melphalan; Doxorubicin; Liposomal doxorubicin; Fludarabine; Fludarabine phosphate; Etoposide; Vincristine; Tacrolimus; Cyclosporins; Fluorodeoxyglucose F18
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Ewing's Sarcoma; Rhabdomyosarcoma; Desmoplastic Small Round Cell Tumor; Sarcoma; Ewing Sarcoma