Mithramycin for Lung, Esophagus, and Other Chest Cancers

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01624090
First received: June 16, 2012
Last updated: March 14, 2014
Last verified: January 2014
  Purpose

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 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.

Condition Intervention Phase
Lung Cancer
Esophageal Cancer
Mesothelioma
Gastrointestinal Neoplasms
Breast Cancer
Drug: Mithramycin
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 45
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)
Intervention Details:
    Drug: Mithramycin
    30 mg/kg IV over 6 h once daily for 7 days, to be repeated every 28 days (one cycle). Two cycles will constitute one course of therapy.
  Hide Detailed Description

Detailed 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 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.

Primary Objective:

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

Eligibility:

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.

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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Diagnosis:

Patients with measurable inoperable, histologically confirmed primary lung and esophageal carcinomas, thymic neoplasms, malignant pleural mesotheliomas or chest wall sarcomas, as well as patients with extra-thoracic malignancies metastatic to lungs, esophagus, pleura or mediastinum are eligible.

Histologic confirmation of disease in the Laboratory of Pathology, CCR, NCI, NIH.

Age > 18.

ECOG status 0-2.

Patients must have had or refused first-line standard chemotherapy for their malignancies.

Patients must have had no chemotherapy, biologic therapy, or radiation therapy for their malignancy for at least 30 days prior to treatment. Patients may have received localized radiation therapy to non-target lesions provided that the radiotherapy is completed 14 days prior to commencing therapy, and the patient has recovered from any toxicity. At least 3 half-lives must have elapsed since monoclonal antibody treatment. At least six weeks must have elapsed between mitomycin C or nitrosourea treatment.

Patients must have adequate organ and marrow function as defined below:

a) Hematologic and Coagulation Parameters:

i. Peripheral ANC greater than or equal to 1500/mm3

ii. Platelets greater than or equal to 100,000/ mm3 (transfusion independent)

iii. Hemoglobin greater than or equal to 8 g/dL (PRBC transfusions permitted)

iv. Normal PT/PTT/fibrinogen with the exception of a lupus anticoagulant, which is permitted.

b) Hepatic Function

i. Bilirubin (total) < 1.5 times upper limit of normal (ULN)

ii. ALT (SGPT) less than or equal to 3.0 times ULN

iii. Albumin > 2 g/dL

c) Renal Function

i. Creatinine within normal institutional limits or creatinine clearance greater than or equal to60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

ii. Normal ionized calcium, magnesium and phosphorus (can be on oral supplementation)

Cardiac Function: Left ventricular ejection fraction (EF) > 40% by Echocardiogram, MUGA, or cardiac MR.

Ability of subject to understand, and be willing to sign informed consent.

Female and male patients (and when relevant their partners) must be willing to practice birth control (including abstinence) during and for two months after treatment, if of childbearing potential during sexual contact with a female of childbearing potential.

Patients must be willing to undergo 2 tumor biopsies

EXCLUSION CRITERIA:

Clinically significant systemic illness (e.g. serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the PI would compromise the patient s ability to tolerate protocol therapy or significantly increase the risk of complications.

Patients with cerebral metastases

Patients with any of the following pulmonary function abnormalities will be excluded: FEV, < 30% predicted; DLCO, < 30% predicted (post-bronchodilator); pO2 < 60 mm Hg or pCO2 greater than or equal to 55 mm Hg on room air arterial blood gas.

Patients with evidence of active bleeding, intratumoral hemorrhage or history of bleeding diatheses, unless specifically occurring as an isolated incident durined reversible chemotherapy induced thrombocytopenia.

Patients on therapeutic anticoagulation. Note: prophylactic anticoagulation (i.e. intralumenal heparin) for venous or arterial access devices is allowed.

Patients who are concurrently receiving or requiring any of the following agents, which may increase the risk for mithramycin related toxicities, such as hemorrhage:

Thrombolytic agents

Aspirin or salicylate-containing products, which may increase risk of hemorrhage

Dextran

Dipyridamole

Sulfinpyrazone

Valproic acid

Clopidogrel

Lactating or pregnant females (due to risk to fetus or newborn, and lack of testing for excretion in breast milk).

Patients with history of HIV, HBV or HCV due to potentially increased risk of mithramycin toxicity in this population.

Hypersensitivity to mithramycin

Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01624090

Contacts
Contact: Tricia Kunst, R.N. (301) 451-1233 kunstt@mail.nih.gov
Contact: David S Schrump, M.D. (301) 496-2128 david_schrump@nih.gov

Locations
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    ncisbirc@mail.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: David S Schrump, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01624090     History of Changes
Other Study ID Numbers: 120151, 12-C-0151
Study First Received: June 16, 2012
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Cancer Stem Cell
Thoracic Malignancies
Mythramycin Treatment
Lung Tumors
Metastatic Lung Tumors

Additional relevant MeSH terms:
Breast Neoplasms
Esophageal Neoplasms
Mesothelioma
Neoplasms, Mesothelial
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Plicamycin
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on September 18, 2014