Description:
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.
Title
- Brief Title: Mithramycin for Lung, Esophagus, and Other Chest Cancers
- Official Title: Phase II Evaluation of Mithramycin, an Inhibitor of Cancer Stem Cell Signaling, in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum
Clinical Trial IDs
- ORG STUDY ID:
120151
- SECONDARY ID:
12-C-0151
- NCT ID:
NCT01624090
Conditions
- Lung Cancer
- Esophageal Cancer
- Mesothelioma
- Gastrointestinal Neoplasms
- Breast Cancer
Interventions
Drug | Synonyms | Arms |
---|
Mithramycin | Mithracin | 1/mithramycin |
Purpose
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.
Detailed Description
Background:
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 Epigenetics Laboratory, Thoracic and Oncology Surgery
Branch (TOSB)/National Cancer Institute (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 malignant pleural mesothelioma
(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 6 hour intravenous
infusions in patients with malignancies involving lungs, esophagus, pleura, or mediastinum.
Eligibility:
- 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.
- Patients with germline single nucleotide polymorphisms (SNPs) in 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) that are associated with resistance to mithramycin-induced
hepatotoxicity.
- Patients must have had or refused first-line standard therapy for their malignancies.
- Patients must be 18 years or older with an Eastern Cooperative Oncology Group (ECOG)
performance status of 0-2, without evidence of unstable or decompensated myocardial
disease. Patients must have adequate pulmonary reserve evidenced by forced expiratory
volume 1 (FEV1) and diffusing capacity for carbon monoxide (DLCO) equal to or greater
than 30% predicted; oxygen saturation greater than or equal to 92% on room air. Arterial
Blood Gas (ABG) will be drawn if clinically indicated.
- Patients must have a platelet count greater than 100,000, an absolute neutrophil count
(ANC) equal to or greater than 1500 without transfusion or cytokine support, a normal
prothrombin time (PT)/partial thromboplastin time (PTT), and adequate hepatic function
as evidenced by a total bilirubin of <1.5 times upper limits of normal (ULN) and
aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than or equal to 3
x ULN. Serum creatinine less than 3 or equal to 1.6 mg/ml, or creatinine clearance
greater than 70 ml/min/1.73m^2.
Design:
- Simon Optimal Two Stage Design for Phase II Clinical Trials targeting an objective
response rate (Response Evaluation Criteria in Solid Tumors (RECIST)) of 30%.
- Patients will be stratified based on location of primary disease (thoracic vs.
extra-thoracic).
- Patients will receive 6 hour infusions of mithramycin at 30 -50 mcg/kg every day for 7
days, every 21 days (1 cycle). Three cycles will constitute one course of therapy. Those
patients tolerating 30 mcg/kg infusions during the first cycle will receive subsequent
cycles of mithramycin at a dose of 50 mcg/kg using the same infusion schedule.
- 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.
Trial Arms
Name | Type | Description | Interventions |
---|
1/mithramycin | Experimental | Single agent intravenous (IV) mithramycin | |
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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Number of Participants With an Objective Response (Complete Response + Partial Response) |
Time Frame: | Every 8 weeks until disease progression or unacceptable toxicity, over an average of 4 months. |
Safety Issue: | |
Description: | Objective response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesion, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
Secondary Outcome Measures
Measure: | Number of Participants With Serious and Non-Serious Adverse Events |
Time Frame: | Date treatment consent signed to date off study, approx. 9 mos & 6 days DL1 30 mcg/kg thoracic group, 2 mos & 16 days DL1 30 mcg/kg extra-thoracic group, 5 mos & 26 days DL-1 25 mcg/kg thoracic group, & 20 days DL-1 25 mcg/kg extra-thoracic group |
Safety Issue: | |
Description: | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). 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. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Terminated |
Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- Cancer Stem Cell
- Thoracic Malignancies
- Mithramycin Treatment
- Lung Tumors
- Metastatic Lung Tumors
Last Updated
December 30, 2019