Tabectedin to Treat Children and Adolescents With Cancer
Condition: Solid Tumors
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

        -  Trabectedin is an experimental drug that kills some cancer cells in the laboratory and
           in mice by interfering with genetic material (DNA) in cancer cells.

        -  In some adult patients with cancer who received trabectedin, tumors grew slower or
           shrank.

      Objectives:

        -  To determine a dose of trabectedin that can be given safely to children and adolescents
           as a 24-hour continuous infusion through a vein.

        -  To determine the side effects of trabectedin in children and adolescents.

        -  To study how the body handles trabectedin by measuring the amount of the drug in the
           bloodstream over time after a dose is given.

        -  To measure the effect of trabectedin on DNA in white blood cells.

        -  To determine if an individual's tumor cells have a specific proteins involved in DNA
           repair and if a pattern of genes can be identified in tumor samples that might help
           explain why trabectedin reduces tumors in some individuals and not others.

        -  To study genetic factors that may influence the way the body handles trabectedin.

        -  To see if trabectedin is beneficial in certain types of cancer.

      Eligibility:

      -Children between 4 year and 17 years of age with tumors that recur or no longer respond to
      standard treatment.

      Design:

        -  Patients receive trabectedin as a 24-hour continuous infusion repeated every 21 days.
           The first three children entering the study receive a dose of 1.1 mg/m2. Subsequent
           groups of up to six patients receive higher doses (1.5 mg/m2 and 1.7 mg/m2) as long as
           the preceding dose is well tolerated. Patients enrolled at the lowest dose level may
           have their dose increased to the next level if they tolerated the lower dose well.
           Treatment may continue as long as the cancer does not worsen and the treatment is
           tolerated.

        -  Patients have blood drawn on days 1, 2, 3, 4, 5 and 7 of the first treatment cycle to
           study how the body handles trabectedin.

        -  A tumor sample obtained from a prior surgery or biopsy is examined for proteins involved
           in DNA repair.

        -  A blood sample is drawn to look for genetic factors that may influence how the body
           handles trabectedin.

        -  Patients have periodic physical examinations and blood tests. MRI or CT scans are done
           before starting therapy and after every two treatment cycles to evaluate the tumor.
    

Detailed description: 
      Background:

      Trabectedin (ET-743) is a natural product derived from the marine tunicate Ecteinascidia
      turbinata. It binds to the minor groove of DNA and interacts with various transcription
      factors resulting in cell cycle arrest. It also inhibits transcription coupled nucleotide
      excision repair system inducing lethal DNA strand breaks.

      In preclinical and clinical studies, trabectedin has been found to be active in many soft
      tissue sarcomas including leiomyosarcoma, synovial cell sarcoma, neuroblastoma,
      rhabdomyosarcoma, melanoma, breast, ovarian, non-small cell lung, renal and prostate
      carcinoma.

      In adult phase I and phase II studies, trabectedin has been well-tolerated up to dose levels
      of 1.9mg/m(2)/dose with the most common toxicities being fatigue, neutropenia, and reversible
      transaminase elevations. Objective responses were seen at doses equal to or greater than
      1.5mg/m(2)/dose. Trabectedin 1.5mg/m(2) administered as a 24-hour continuous intravenous
      infusion is the recommended dose and schedule in adults.

      A pediatric phase I study of trabectedin administered as a 3-hour infusion has been completed
      in the Children's Oncology Group. The maximum tolerated dose was 1.1 mg/m(2). Dose limiting
      toxicity was reversible elevation of hepatic transaminases.

      Objectives:

      Determine the maximum tolerated dose (MTD) of trabectedin administered as a 24-hour
      continuous infusion in children and adolescents with relapsed or refractory solid tumors.

      Define the toxicity profile of trabectedin administered as a 24-hr infusion in children and
      adolescents.

      Describe the pharmacokinetics of trabectedin administered as a 24-hr infusion in children and
      adolescents.

      Quantify double strand DNA breaks in peripheral blood mononuclear cells of patients receiving
      trabectedin.

      Evaluate archival formalin fixed paraffin embedded tumor tissue, when available from prior
      biopsies or surgical procedures, for the expression of the nucleotide excision repair
      proteins and genomic instability markers (histone gamma-H2AX, phospho-ATM, phospho-Chk2) by
      immunohistochemistry

      Molecular characterization of DNA repair genes and correlation to outcome using mRNA isolated
      from microdissected archival formalin fixed, paraffin embedded tumor sections.

      Study the pharmacogenetics of host DNA repair proteins and drug metabolizing enzymes to
      explore the impact of host factors on trabectedin toxicity.

      Eligibility:

      Children greater than or equal to 4 years and less than 17 years of age with relapsed or
      refractory solid tumors.

      Design:

      Patients will receive trabectedin as a 24-hour continuous infusion repeated every 21 days.
      The starting dose level is 1.1mg/m(2)/dose with escalations to 1.5mg/m(2)/dose and
      1.7mg/m(2)/dose.

      All patients will receive dexamethasone pretreatment and growth factor support with
      filgrastim or pegfilgrastim.

      The definition of dose-limiting hepatic toxicity will be identical to the definition used in
      phase I trials in adults on the same dosing schedule.

      Pharmacokinetic analysis will be performed on days 1, 2, 3, 4, 5 and 7 of the first treatment
      cycle.

      Three to six patients will be enrolled at the first dose level and up to 6 patients will be
      enrolled on subsequent dose levels. Dose escalation will be based on tolerability of
      trabectedin at the prior dose level. For patients enrolled at dose level 1 (1.1mg/m(2)),
      intrapatient dose escalation to dose level 2 (1.5mg/m(2)) will be allowed with subsequent
      cycles if no dose limiting toxicities occurred at the lower dose level. Total accrual will be
      up to 24 patients.
    

Intervention name(s): Trabectedin (ecteinascidin-743, ET-743, YONDELIS [R])
Intervention type(s): Drug
Intervention MeSH terms: Trabectedin
Primary purpose: Treatment
Keywords: DNA Repair; Nucleotide Excision Repair; Trabectedine; Phase I; Sarcoma; Cytotoxic; Chemotherapy; Solid Tumor; Malignant Tumor; Rhabdomyosarcoma; Ewing Sarcoma; Neuroblastoma; Wilm's Tumor; Hepatic Tumor; Brain Tumor