Mithramycin for Lung, Esophagus, and Other Chest Cancers
Condition: Lung Cancer; Esophageal Cancer; Mesothelioma; Gastrointestinal Neoplasms; Breast Cancer
MeSH terms: Mesothelioma; Gastrointestinal Neoplasms; Digestive System Neoplasms
Intervention: Mithramycin
Intervention description: 30 mcg/kg intravenous (IV) over 6 hours once daily for 7 days, to be repeated every 21 days (one cycle) until disease progression or unacceptable toxicity
Intervention MeSH terms: Plicamycin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cancer Stem Cell; Thoracic Malignancies; Mithramycin Treatment; Lung Tumors; Metastatic Lung Tumors

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Diagnosis: 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

          -  Histologic confirmation of disease in the Laboratory of Pathology, Center for Cancer
             Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH).

          -  Disease amenable to biopsy via percutaneous approach or other minimally invasive
             procedures such as thoracoscopy, bronchoscopy, laparoscopy, or gastrointestinal (GI)
             endoscopy

          -  Age >18

          -  Eastern Cooperative Oncology Group (ECOG) status 0-2.

          -  Patients must have had or refused first-line standard chemotherapy for their
             inoperable 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 absolute neutrophil count (ANC) greater than or equal to 1500/mm^3

        ii. Platelets greater than or equal to 100,000/ mm^3 (transfusion independent)

        iii. Hemoglobin greater than or equal to 8 g/dL (peripheral red blood count (PRBC)
        transfusions permitted)

        iv. Prothrombin Time (PT)/Partial Thromboplastin Time (PTT) within normal limits (patient
        may be eligible for trial if abnormality is deemed clinically insignificant and cleared for
        protocol therapy by Hematology Consult Service)

        b) Hepatic Function

        i. Bilirubin (total) < 1.5 times upper limit of normal (ULN)

        ii. Alanine aminotransferase (ALT) (Serum glutamic pyruvic transaminase (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 to 60 mL/min/1.73 m^2 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,
             multi-gated acquisition scan (MUGA), or cardiac magnetic resonance (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:

          -  Patients with adenosine 5-triphosphate binding cassette subfamily B member 4 (ABCB4),
             adenosine 5-triphosphate binding cassette subfamily B member 11 (ABCB11),
             retinal-binding protein (RALBP) or cytochrome P851 (CYP851) genotypes associated with
             mithramycin-mediated hepatotoxicity.

          -  Clinically significant systemic illness (e.g. serious active infections or significant
             cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the
             Principal Investigator (PI) would compromise the patients 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:
             forced expiratory volume (FEV), < 30% predicted; diffusing capacity for carbon
             monoxide (DLCO), < 30% predicted (post-bronchodilator); Oxygen saturation greater than
             92% on room air. Arterial Blood Gas will be drawn if clinically indicated.

          -  Patients with evidence of active bleeding, intratumoral hemorrhage or history of
             bleeding diatheses, unless specifically occurring as an isolated incident during
             reversible chemotherapy induced thrombocytopenia

          -  Patients on therapeutic anticoagulation. Note: prophylactic anticoagulation (i.e.
             intraluminal 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 Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV)
             or Hepatitis C Virus (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