Stem Cell Transplantation in Patients With High-Risk and Recurrent Pediatric Sarcomas
Condition: Sarcoma
MeSH terms: Sarcoma
Intervention: 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 description: 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.
Intervention MeSH terms: Cyclosporine; Sirolimus; Prednisone; Cyclophosphamide; Melphalan; Doxorubicin; Liposomal doxorubicin; Fludarabine; Fludarabine phosphate; Etoposide; Vincristine; Tacrolimus; Cyclosporins; Fluorodeoxyglucose F18
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 60.0
Sex: All
Minimum age: 5 Years
Maximum age: 35 Years
Healthy volunteers: No
Keywords: Ewing's Sarcoma; Rhabdomyosarcoma; Desmoplastic Small Round Cell Tumor; Sarcoma; Ewing Sarcoma

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA: PATIENT

        The following diagnoses will be considered:

          1. 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.

          2. 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.