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Continuous 24h Intravenous Infusion of Mithramycin, an Inhibitor of Cancer Stem Cell Signaling, in People With Primary Thoracic Malignancies or Carcinomas, Sarcomas or Germ Cell Neoplasms With Pleuropulmonary Metastases

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ClinicalTrials.gov Identifier: NCT02859415
Recruitment Status : Suspended
First Posted : August 9, 2016
Last Update Posted : July 24, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Mithramycin is a new cancer drug. In another study, people with chest cancer took the drug 6 hours a day for 7 straight days. Many of them had liver damage as a side effect. It was discovered that only people with certain genes got this side effect. Researchers want to test mithramycin in people who do not have those certain genes.

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Objectives:

To find the highest safe dose of mithramycin that can be given to people with chest cancer who have certain genes over 24 hours instead of spread out over a longer period of time. To see if mithramycin given as a 24-hour infusion shrinks tumors.

Eligibility:

People ages 18 and older who have chest cancer that is not shrinking with known therapies, and whose genes will limit the chance of liver damage from mithramycin

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Lung and heart function tests

X-rays or scans of their tumor

Liver ultrasound

Tumor biopsy

Participants will be admitted to the hospital overnight. A small plastic tube (catheter) will be inserted in the arm or chest. They will get mithramycin through the catheter over about 24 hours.

If they do not have bad side effects or their cancer does not worsen, they can repeat the treatment every 14 days.

Participants will have multiple visits for each treatment cycle. These include repeats of certain screening tests.

After stopping treatment, participants will have weekly visits until they recover from any side effects.


Condition or disease Intervention/treatment Phase
Esophageal Neoplasms Lung Neoplasms Mesothelioma Thymus Neoplasms Neoplasms, Germ Cell and Embryonal Drug: Mithramycin Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Evaluation of Continuous 24h Intravenous Infusion of Mithramycin, an Inhibitor of Cancer Stem Cell Signaling, in Patients With Primary Thoracic Malignancies or Carcinomas, Sarcomas or Germ Cell Neoplasms With Pleuropulmonary Metastases
Study Start Date : August 6, 2016
Estimated Primary Completion Date : August 3, 2028
Estimated Study Completion Date : August 3, 2028


Arm Intervention/treatment
Experimental: Phase I
Escalating doses of MithramycinPhase 1: 24 hour intravenous infusion of mithramycin given once every 14 days at escalating doses
Drug: Mithramycin
Phase 1: 24 hour intravenous infusion of mithramycin given once every 14 days at escalating doses; Phase 2: 24 hour intravenous infusion of mithramycin given once every 14 days at MTD established in phase 1

Experimental: Phase II
Mithramycin administered at MTDPhase 2: 24 hour intravenous infusion of mithramycin given once every 14 days at MTD
Drug: Mithramycin
Phase 1: 24 hour intravenous infusion of mithramycin given once every 14 days at escalating doses; Phase 2: 24 hour intravenous infusion of mithramycin given once every 14 days at MTD established in phase 1




Primary Outcome Measures :
  1. Maximum tolerated dose [ Time Frame: at the end of first 14 day cycle at each dose level ]
    The number of patients experiencing DLT.Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity.

  2. Overall response rate [ Time Frame: every 8 weeks until at disease progression ]
    Response rates will be calculated as the percent of patients whose best response is a CR or PR.



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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Diagnosis: Patients with measurable inoperable, histologically confirmed non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), esophageal carcinoma, thymic epithelial neoplasms, germ cell tumors, malignant pleural mesotheliomas or chest wall sarcomas, as well as patients with gastric, colorectal, pancreas or renal cancers, germ cell tumors and sarcomas metastatic to thorax are eligible.
  • Histologic confirmation of disease in the Laboratory of Pathology, CCR, NCI, NIH.
  • Germline ABCB4 (CC) and ABCB11 (GG or GC) genotypes determined by pharmacogenomics analysis of peripheral blood mononuclear cells.
  • Disease amenable to biopsy via percutaneous approach or other minimally invasive procedures such as thoracoscopy, bronchoscopy, laparoscopy, or GI endoscopy
  • Age greater than or equal to18
  • 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:

    1. Hematologic and Coagulation Parameters:

      • Peripheral ANC greater than or equal to 1500/mm(3)
      • Platelets greater than or equal to 100,000/ mm(3) (transfusion independent)
      • Hemoglobin greater than or equal to 8 g/dL (PRBC transfusions permitted)
      • PT/PTT within normal limits ( 11.6 - 15.2 / 25.3 - 37.3 sec)
    2. Hepatic Function

      • Bilirubin (total) < 1.5 times upper limit of normal (ULN)
      • ALT (SGPT) less than or equal to 3.0 times ULN
      • Albumin > 2 g/dL
    3. Renal Function

      • 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.
      • 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 female of childbearing potential or male having 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 during 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02859415


Locations
United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: David S Schrump, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02859415     History of Changes
Other Study ID Numbers: 160152
16-C-0152
First Posted: August 9, 2016    Key Record Dates
Last Update Posted: July 24, 2018
Last Verified: July 20, 2018

Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Metastatic Colorectal Cancer
Metastatic Renal Cell Cancer
Sarcoma
ABCB4 Liver Toxicity
ABCB11 Heptatoxicity

Additional relevant MeSH terms:
Neoplasms
Sarcoma
Mesothelioma
Lung Neoplasms
Esophageal Neoplasms
Neoplasms, Germ Cell and Embryonal
Thymus Neoplasms
Thymoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms, Mesothelial
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Gastrointestinal Neoplasms
Digestive System Neoplasms
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Lymphatic Diseases
Neoplasms, Complex and Mixed
Plicamycin
Antibiotics, Antineoplastic
Antineoplastic Agents
Protein Synthesis Inhibitors