Mithramycin for Lung, Esophagus, and Other Chest Cancers
- Mithramycin is a drug that was first tested as a cancer therapy in the 1960s. It acted against some forms of cancer, but was never accepted as a treatment. Research suggests that it may be useful against some cancers of the chest, such as lung and esophageal cancer or mesothelioma. Researchers want to see if mithramycin can be used to treat these types of cancer.
- To see if mithramycin is safe and effective against different chest cancers.
- Individuals at least 18 years of age who have lung, esophagus, pleura, or mediastinum cancers.
- Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and tumor tissue samples will be used to monitor the cancer before treatment.
- Participants will receive mithramycin every day for 7 days, followed by 14 days without treatment. Each 28-day round of treatment is called a cycle.
- Treatment will be monitored with frequent blood tests and imaging studies.
- Participants will continue to take the drug for as long as the side effects are not severe and the tumor responds to treatment.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Evaluation of Mithramycin, an Inhibitor of Cancer Stem Cell Signaling, in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum|
- To assess clinical response rates of mithramycin administered as 6h intravenous infusions in patients with malignancies involving lungs, esophagus, pleura, or mediastinum. [ Time Frame: 6 years ] [ Designated as safety issue: No ]
- toxicity will be assessed as per common terminology criteria for adverse event (CTCAE) version 4 [ Time Frame: from time of administration of first dose through 30 days following administrati ] [ Designated as safety issue: Yes ]
- To determine PK and toxicities; 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 post- treatment tumor biopsies... [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
|Study Start Date:||June 2012|
|Estimated Study Completion Date:||July 2018|
|Estimated Primary Completion Date:||July 2018 (Final data collection date for primary outcome measure)|
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 tumor biopsies.
To compare gene expression and microRNA profiles in patient biopsies with expression signatures corresponding with in-vitro and in-vivo treatment responses in preclinical studies.
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 than 3
or equal to 1.6 mg/ml, or creatinine clearance greater than 70 ml/min/1.73m2 at the time vaccination commences.
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. extra-thoracic).
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.
|Contact: Tricia Kunst, R.N.||(301) firstname.lastname@example.org|
|Contact: David S Schrump, M.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center 866-820-4505 firstname.lastname@example.org|
|Principal Investigator:||David S Schrump, M.D.||National Cancer Institute (NCI)|