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

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 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).

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 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 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 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 had no more than 2 prior cytotoxic chemotherapy regimens, excluding non-myeloablative chemotherapy.

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

1. Hematologic and Coagulation Parameters:
   1. Peripheral ANC greater than or equal to 1500/mm3
   2. Platelets greater than or equal to 100,000/ mm3 (transfusion independent)
   3. Hemoglobin greater than or equal to 8 g/dL (PRBC transfusions permitted)
   4. Normal PT/PTT/fibrinogen with the exception of a lupus anticoagulant, which is permitted.
2. Hepatic Function
   1. Bilirubin (total) < 1.5 times upper limit of normal (ULN)
   2. ALT (SGPT) less than or equal to 3.0 times ULN
   3. Albumin > 2 g/dL
3. Renal Function
   1. 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.
   2. iNormal 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 and:

• Have disease amenable to biopsy via percutaneous approach or other minimally invasive procedures such as thoracoscopy, bronchoscopy, laparoscopy, or GI endoscopy
• Hematologic and coagulation parameters within 7 days prior to baseline biopsy, and within two days prior to biopsies while on therapy: Normal PT/PTT with exception of lupus anticoagulant, platelets greater than or equal to75,000/ microL, peripheral ANC greater than or equal to750/microL

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.