Phase I/II Trial of Mithramycin in Children and Adults With Refractory Extracranial Solid Tumors (Phase I) or Ewing Sarcoma and EWSFLI1 Fusion Transcript (Phase II)
- Mithramycin, an anti-tumor antibiotic, underwent broad clinical evaluation in solid
tumors and leukemias in the 1960's 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.
Therefore, there is a need for effective novel agents for the treatment of this
- 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.
- Phase I portion of this study is to: 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 is to: determine the objective response rate (CR and PR)
of Ewing sarcoma to mithramycin in children and adults using RECIST criteria when
administered at 17.5 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 to: 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 greater than or equal to 18 years old with
Ewing sarcoma and EWS/FLI1 fusion transcript with disease amenable to percutaneous
- Phase I Portion: children (greater than or equal to 12 months) and adolescents (less
than or equal to 17 years) with recurrent or refractory extracranial solid tumors.
- Phase II Portion in adults: adults (greater than or equal to 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,
(greater than or equal to 12 months) and adolescents (less than or equal to 17 years) with
recurrent or refractory measurable
extracranial Ewing sarcoma and the EWS-FLI1 fusion transcript will begin enrollment to the
Phase II portion.
- Participants must meet safety laboratory criteria and prior therapy limitations.
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 greater than or equal to 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 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated
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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Phase I: determine the tolerability, toxicity, and recommended dose of mithramycin in pediactric patients with extracranial tumors.
Brigitte C Widemann, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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