Phase II Evaluation of Mithramycin, an Inhibitor of Cancer Stem Cell Signaling, in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum
Increasing evidence indicates that activation of stem cell gene expression is a common
mechanism by which environmental carcinogens mediate initiation and progression of thoracic
malignancies. Similar mechanisms appear to contribute to extra-thoracic malignancies that
metastasize to the chest. Utilization of pharmacologic agents, which target gene regulatory
networks mediating stemness may be novel strategies for treatment of these neoplasms.
Recent studies performed in the Thoracic Oncology Laboratory, SB/NCI, demonstrate that under
exposure conditions potentially achievable in clinical settings, mithramycin diminishes stem
cell gene expression and markedly inhibits growth of lung and esophageal cancer and MPM
cells in vitro and in vivo. These finding add to other recent preclinical studies
demonstrating impressive anti-tumor activity of mithramycin in epithelial malignancies and
sarcomas that frequently metastasize to the thorax.
To assess clinical response rates of mithramycin administered as 6hour intravenous
infusionsin patients with malignancies involving lungs, esophagus, pleura, or mediastinum.
To determine pharmacokinetics and toxicities of mithramycin administered as 6hour
intravenous infusions in patients with inoperable thoracic malignancies. To ascertain if
mithramycin inhibits cancer stem cell signaling in patients with thoracic malignancies.
To evaluate gene expression, DNA methylation and micro-RNA profiles in pre- and osttreatment
To compare gene expression and microRNA profiles in patient biopsies with expression
signatures corresponding with in-vitro and in-vivo treatment responses in preclinical
To examine if mithramycin decreases cancer stem cells.
To develop methodologies for assessing effects of mithramycin on cancer stem cells,
hematopoietic stem cells, mesenchymal stem cells, and circulating tumor cells (CTC).
Patients with histologically or cytologically proven primary malignancies involving lungs,
esophagus, pleura or mediastinum, or extra-thoracic malignancies metastatic to the chest.
Patients must have had or refused first-line standard therapy for their malignancies.
Patients must be 18 years or older with an ECOG performance status of 0 - 2, without
evidence of unstable or decompensated myocardial disease. Patients must have adequate
pulmonary reserve evidenced by FEV1 and DLCO equal to or greater than 30% predicted; pCO(2)
less than 55 mm Hg and pO(2) greater than 60 mm Hg on room air ABG.
Patients must have a platelet count greater than 100,000, an ANC equal to or greater than
1500 without transfusion or cytokine support, a normal PT, and adequate hepatic function as
evidenced by a total bilirubin of < 1.5 times upper limits of normal. Serum creatinine less
or equal to 1.6 mg/ml, or creatinine clearance greater than 70 ml/min/1.73m2 at the time
Simon Optimal Two Stage Design for Phase II Clinical Trials targeting an objective response
rate (RECIST) of 30%.
Patients will be stratified based on location of primary disease (thoracic vs.
Patients will receive 6hour infusions of mithramycin at 30 mcg/kg every day for 7 days,
every 28 days (1 cycle). Two cycles will constitute one course of therapy.
Following each course of therapy, patients will undergo restaging studies. Patients
exhibiting objective response to therapy or stable disease by RECIST criteria will be
offered an additional course of therapy.
Patients exhibiting disease progression will be removed from study.
Biopsies of index lesions will be obtained at baseline and on day 8 of the second cycle of
therapy for analysis of molecular end-points.
Pharmacokinetics will be assessed during cycle 1 and cycle 2 of the first course of therapy.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To assess clinical response rates of mithramycin administered as 6h intravenous infusions in patients with malignancies involving lungs, esophagus, pleura, or mediastinum.
David S Schrump, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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