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Pediatric Cancers

Phase I/II Trial of Mithramycin In Children and Adults With Refractory Extracranial Solid Tumors (Phase I) or Ewing Sarcoma and EWS-FLI1 Fusion Transcript

NCI-12-C-0135, NCT01610570

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Investigator(s):

Brigitte Widemann, M.D.
Principal Investigator
Phone: 301-496-7387
widemanb@mail.nih.gov

Referral Contact(s):

Pediatric Oncology
Phone: 301-496-4256
1-877-624-4878 (Toll free)

 

Background:

  • Activation mithramycin, an anti-tumor antibiotic, underwent broad clinical evaluation in solid tumors and leukemias in the 1960s and demonstrated activity in some leukemias, lymphomas, and solid tumors; in particular, mithramycin was found to have activity against testicular cancers and was briefly used in the clinic for this tumor prior to the development of the currently used treatment regimen
  • The Ewing Sarcoma Family of Tumors (ESFT) is the second most common malignant bone tumor of childhood; there has been very little improvement in overall patient survival in past years, particularly for patients with high-risk metastatic or relapsed disease, so there is a need for effective novel agents for the treatment of this disease
  • Multiple studies have shown that suppressing the expression of EWS-FLI1 effectively limits the tumorigenicity of ESFT cells; laboratory studies have shown that mithramycin effectively suppresses the activity of EWS-FLI1 both in vitro and in vivo

Objectives:

    • Primary Objectives:
      • Phase I portion of this study: Determine the tolerability, toxicity, and the recommended phase II dose of mithramycin in children and adolescents with refractory extracranial solid tumors
      • Phase II portion of this trial: Determine the objective response rate (CR and PR) of Ewing sarcoma to mithramycin in children and adults using RECIST criteria when administered at 25 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression
      • Phase II portion of this trial: Evaluate if mithramycin inhibits NR0B1 in tumor tissue and determine changes in gene expression signature pre-treatment and at steady state on Day +4 of treatment in patients ≥ 18 years old with Ewing sarcoma and EWS/FLI1 fusion transcript with disease amenable to percutaneous biopsy

      Key Eligibility Criteria:

      • Phase I portion: Children (≥ 12 months) and adolescents (≤ 17 years) with recurrent or refractory extracranial solid tumors
      • Phase II portion in adults: Adults (≥ 18 years of age at enrollment) with recurrent or refractory measurable extracranial Ewing sarcoma and the EWS-FLI1 fusion transcript
      • Phase II portion in children and adolescents: Once the adult dose is deemed safe, children (≥ 12 months) and adolescents (≤ 17 years of years) with recurrent or refractory measurable extracranial Ewing sarcoma and the EWS-FLI1 fusion transcript will begin enrollment to the Phase II portion
      • All participants must meet safety laboratory criteria and prior therapy limitations

      Study Outline:

        • Phase I Portion
          • Mithramycin will be administered in escalating doses to children and adolescents intravenously over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression
          • The cohort at the recommended dose or MTD will be expanded up to 12 patients, and attempts will be made to enroll 6 patients that are ≥ 12 years of age and 6 patients that are < 12 years of age to gain experience with a broad age range of patients
          • A maximum of 18 evaluable patients will be enrolled on the phase I portion
        • Phase II Portion
          • Using a Simon two stage design, mithramycin will be administered intravenously at 25 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with EWS-FLI1 fusion transcript
          • Up to 24 evaluable patients will be enrolled on the phase II portion
        • The Phase I and Phase II portions of the protocol will enroll patients simultaneously

          Additional Information:

          • This trial will be conducted at the NIH Clinical Center in Bethesda, MD. It is open to patients who meet the eligibility requirements, regardless of where they live in the United States.
          • There is no charge for medical care received at NIH Clinical Center.
          • PDQ (Physicians Data Query) - provides additional details about this study for health care providers.


          Reviewed: 12/14/12
          Updated: 6/11/12

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