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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 : Terminated (Slow/Insufficient accrual)
First Posted : August 9, 2016
Results First Posted : April 5, 2022
Last Update Posted : April 5, 2022
Sponsor:
Information provided by (Responsible Party):
David Schrump, M.D., 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.

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Allocation: Non-Randomized
Intervention Model: Sequential 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
Actual Study Start Date : August 8, 2019
Actual Primary Completion Date : December 6, 2019
Actual Study Completion Date : December 1, 2021


Arm Intervention/treatment
Experimental: Phase I/Escalating doses of Mithramycin
Escalating doses of Mithramycin
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
Other Name: Plicamycin

Experimental: Phase II/Mithramycin administered at Maximum Tolerated Dose (MTD)
Mithramycin administered 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
Other Name: Plicamycin




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: At the end of first 14 day cycle at each dose level ]
    MTD is defined as the number of participants experiencing a dose-limiting toxicity (DLT). A DLT is defined as Grade 4 or greater anemia or neutropenia exceeding 5 days duration, thrombocytopenia requiring transfusion, or Grade 3 or greater nonhematologic toxicity possibly, probably, or definitely related to the investigational therapy excluding alopecia during Cycle 1 of therapy.

  2. Number of Participants Whose Best Response is a Complete Response (CR) or Partial Response (PR) [ Time Frame: every 8 weeks until at disease progression, approximately 3.5 months ]
    Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.


Secondary Outcome Measures :
  1. To Ascertain if Mithramycin Inhibits Stem Cell Gene Expression in Participants With Thoracic Malignancies [ Time Frame: baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1 ]
    Studies on tumor tissue obtained during baseline /previous biopsy (if available), Cycle 1 Day 4(+/- 3 days), and possible treatment evaluation following Course 1. Plasma and blood will also be collected.

  2. To Evaluate Gene Expression, Deoxyribonucleic Acid (DNA) Methylation and Micro-ribonucleic Acid (RNA) Profiles in Pre- and Post-treatment Tumor Biopsies [ Time Frame: baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1 ]
    Studies on tumor tissue obtained during baseline /previous biopsy (if available), Cycle 1 Day 4(+/- 3 days), and possible treatment evaluation following Course 1.

  3. To Compare Gene Expression, Deoxyribonucleic Acid (DNA) Methylation and Micro-ribonucleic Acid (RNA) Profiles in Participant Tumor Biopsies With Treatment Response Profiles in Pre-clinical Studies [ Time Frame: baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1 ]
    Studies on tumor tissue obtained during baseline /previous biopsy (if available), Cycle 1 Day 4(+/- 3 days), and possible treatment evaluation following Course 1.

  4. To Examine if Mithramycin Decreases Pluripotent Cancer Stem Cells (Side Population) [ Time Frame: baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1 ]
    Studies on tumor tissue obtained during baseline /previous biopsy (if available), Cycle 1 Day 4(+/- 3 days), and possible treatment evaluation following Course 1.

  5. To Develop Methodologies for Assessing Effects of Mithramycin on Cancer Stem Cells, Hematopoietic Stem Cells, Mesenchymal Stem Cells, and Circulating Tumor Cells (CTC) [ Time Frame: baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1 ]
    Studies on tumor tissue obtained during baseline /previous biopsy (if available), Cycle 1 Day 4(+/- 3 days), and possible treatment evaluation following Course 1. Plasma and blood will also be collected.


Other Outcome Measures:
  1. Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) [ Time Frame: Date treatment consent signed to date off study, approximately 1 month and 4 days, and 3 months and 17 days for the first and second group respectively. ]
    Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

  2. Number of Participants With a Dose-limiting Toxicity (DLT) [ Time Frame: Cycle 1 ]
    A DLT is defined as Grade 4 or greater anemia or neutropenia exceeding 5 days duration, thrombocytopenia requiring transfusion, or Grade 3 or greater nonhematologic toxicity possibly, probably, or definitely related to the investigational therapy excluding alopecia during Cycle 1 of therapy.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients with measurable inoperable, histologically confirmed non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), esophageal carcinomas, thymic neoplasms, germ cell tumors, malignant pleural mesotheliomas or chest wall sarcomas, as well as patients with gastric, colorectal, pancreas or renal cancers, and sarcomas metastatic to thorax.
  • 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 6 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 absolute neutrophil count (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)
      • 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)
    2. Hepatic Function

      • Bilirubin (total) < 1.5 times upper limit of normal (ULN)
      • Alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase(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, multigated 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 2 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:

  • Patients with unfavorable ATP Binding Cassette Subfamily B Member 4 (ABCB11), Ral binding protein (RALBP) or Cytochrome P450 Family 8 Subfamily B Member 1 (CYP8B1) 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 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: forced expiratory volume (FEV), < 30% predicted; diffusing capacity for carbon monoxide (DLCO), < 30% predicted (post-bronchodilator); Oxygen saturation less than or equal to 92% on room air (per vital sign measurement). 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.

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

Documents provided by David Schrump, M.D., National Cancer Institute (NCI):
Informed Consent Form  [PDF] December 29, 2020

Additional Information:
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Responsible Party: David Schrump, M.D., Principal Investigator, National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02859415    
Other Study ID Numbers: 160152
16-C-0152
First Posted: August 9, 2016    Key Record Dates
Results First Posted: April 5, 2022
Last Update Posted: April 5, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by David Schrump, M.D., National Cancer Institute (NCI):
Metastatic Colorectal Cancer
Sarcoma
ABCB4 Liver Toxicity
ABCB11 Hepatotoxicity
Metastatic Renal Cancer
Additional relevant MeSH terms:
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Neoplasms
Sarcoma
Mesothelioma
Lung Neoplasms
Esophageal Neoplasms
Neoplasms, Germ Cell and Embryonal
Thymus Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Connective and Soft Tissue
Adenoma
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
Plicamycin
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antineoplastic Agents
Protein Synthesis Inhibitors