Clinical trial NCT01624090: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Lung Cancer
Esophageal Cancer
Mesothelioma
Gastrointestinal Neoplasms
Breast Cancer
Keywords: Cancer Stem Cell
Thoracic Malignancies
Mithramycin Treatment
Lung Tumors
Metastatic Lung Tumors
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-06-20
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

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

Primary outcomes:
measure: Number of Participants With an Objective Response (Complete Response + Partial Response)
timeFrame: Every 8 weeks until disease progression or unacceptable toxicity, over an average of 4 months.
Secondary outcomes:
measure: Number of Participants With Serious and Non-Serious Adverse Events
timeFrame: 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
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: David S Schrump, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Centers for Disease Control and Prevention (CDC). Smoking-attributable mortality, years of potential life lost, and productivity losses--United States, 2000-2004. MMWR Morb Mortal Wkly Rep. 2008 Nov 14;57(45):1226-8.
citation: Zhai R, Chen F, Liu G, Su L, Kulke MH, Asomaning K, Lin X, Heist RS, Nishioka NS, Sheu CC, Wain JC, Christiani DC. Interactions among genetic variants in apoptosis pathway genes, reflux symptoms, body mass index, and smoking indicate two distinct etiologic patterns of esophageal adenocarcinoma. J Clin Oncol. 2010 May 10;28(14):2445-51. doi: 10.1200/JCO.2009.26.2790. Epub 2010 Apr 12.
citation: Wright CD, Kucharczuk JC, O'Brien SM, Grab JD, Allen MS; Society of Thoracic Surgeons General Thoracic Surgery Database. Predictors of major morbidity and mortality after esophagectomy for esophageal cancer: a Society of Thoracic Surgeons General Thoracic Surgery Database risk adjustment model. J Thorac Cardiovasc Surg. 2009 Mar;137(3):587-95; discussion 596. doi: 10.1016/j.jtcvs.2008.11.042.