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Phase II Evaluation of Mithramycin, an Inhibitor of Cancer Stem Cell Signaling, in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum

Phase 2
18 Years
Open (Enrolling)
Lung Cancer, Esophageal Cancer, Mesothelioma, Gastrointestinal Neoplasms, Breast Cancer

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Trial Information

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.

Primary Objective:

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

Secondary Objectives:

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

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.

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.

Inclusion Criteria



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

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


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




Valproic acid


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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Time Frame:

6 years

Safety Issue:


Principal Investigator

David S Schrump, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

June 2012

Completion Date:

July 2018

Related Keywords:

  • Lung Cancer
  • Esophageal Cancer
  • Mesothelioma
  • Gastrointestinal Neoplasms
  • Breast Cancer
  • Cancer Stem Cell
  • Thoracic Malignancies
  • Mythramycin Treatment
  • Lung Tumors
  • Metastatic Lung Tumors
  • Breast Neoplasms
  • Neoplasms
  • Esophageal Diseases
  • Esophageal Neoplasms
  • Gastrointestinal Neoplasms
  • Digestive System Neoplasms
  • Lung Neoplasms
  • Mesothelioma



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892