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Clinical Trial Summary

Background:

- 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.

Objectives:

- To see if mithramycin is safe and effective against different chest cancers.

Eligibility:

- Individuals at least 18 years of age who have lung, esophagus, pleura, or mediastinum cancers.

Design:

- 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 7 days without treatment. Each 14-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.


Clinical Trial Description

Background:

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 Epigenetics Laboratory, TOSB/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.

Primary Objective:

-To assess clinical response rates of mithramycin administered as 6 hour intravenous infusions in patients with malignancies involving lungs, esophagus, pleura, or mediastinum.

Eligibility:

- Patients with measurable inoperable, histologically confirmed primary lung and esophageal carcinomas, thymic neoplasms, germ cell tumors, malignant pleural mesotheliomas or chest wall sarcomas, as well as patients with gastric, colorectal or renal cancers and sarcomas metastatic to the thorax are eligible.

- Patients with germline SNPs in ABCB4, ABCB11, RALBP or CYP851 that are associated with resistance to mithramycin-induced hepatotoxicity.

- 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; oxygen saturation greater than or equal to 92% on room air. ABG will be drawn if clinically indicated.

- 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/PTT, and adequate hepatic function as evidenced by a total bilirubin of <1.5 times upper limits of normal (ULN) and AST/ALT less than or equal to 3 x ULN. Serum creatinine less than 3 or equal to 1.6 mg/ml, or creatinine clearance greater than 70 ml/min/1.73m^2.

Design:

- 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 6 hour infusions of mithramycin at 30 -50 mcg/kg every day for 7 days, every 21 days (1 cycle). Three cycles will constitute one course of therapy. Those patients tolerating 30 mcg/kg infusions during the first cycle will receive subsequent cycles of mithramycin at a dose of 50 mcg/kg using the same infusion schedule.

- 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. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT01624090
Study type Interventional
Source National Institutes of Health Clinical Center (CC)
Contact Tricia Kunst, R.N.
Phone (240) 760-6234
Email kunstt@mail.nih.gov
Status Recruiting
Phase Phase 2
Start date September 6, 2012
Completion date December 31, 2030

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