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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

Mithramycin

David S Schrump, M.D.

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.

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, 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 findings 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 Objectives:

* Phase I component: To determine pharmacokinetics, toxicities, and maximum tolerated dose (MTD) of mithramycin administered as a continuous 24h infusion in patients with primary thoracic malignancies or carcinomas, sarcomas or germ cell tumors metastatic to the chest.
* Phase II component: To determine objective response rates (Complete Response (CR) + Partial Response (PR) of mithramycin administered as 24h intravenous infusions in patients with primary thoracic malignancies or carcinomas, sarcomas or germ cell tumors metastatic to the chest.

Eligibility:

* Patients with measurable inoperable, histologically confirmed 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 favorable germline single nucleotide polymorphisms (SNPs) in ATP Binding Cassette Subfamily B Member 4 (ABCB4), ATP Binding Cassette Subfamily B Member 11 (ABCB11), Ral binding protein (RALBP) or Cytochrome P450 Family 8 Subfamily B Member 1 (CYP8B1) 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 (FEV1) and diffusing capacity for carbon monoxide (DLCO) equal to or greater than 30% predicted; Oxygen saturation \>= 92% on room air. ABG will be drawn if clinically indicated.
* Patients must have a platelet count greater than or equal to 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 x upper limits of normal (ULN) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \<= 3 X ULN.
* Serum creatinine within normal institutional limits or creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal.

Design:

* Single arm Phase I dose escalation to define pharmacokinetics, toxicities and maximum tolerated dose (MTD).
* Patient cohorts will receive 24hour(h) infusions of mithramycin targeting total doses previously administered during 7 daily six hour infusions at 30-50 mcg/kg.
* The 24h infusions will be administered every 14 days (1 cycle). Four cycles will constitute one course of therapy.
* Pharmacokinetics and toxicity assessment to define MTD will be assessed during Cycle 1 of the first course of therapy.
* Due to uncertainties regarding potential cumulative toxicities, no intra-patient dose escalation will be allowed.
* Once MTD has been defined, patients will be enrolled into two cohorts (primary thoracic malignancy vs neoplasm of non-thoracic origin metastatic to the chest) to determine clinical response rates at the MTD, using a Simon Optimal Two Stage Design for Phase II Clinical Trials targeting an objective response rate (Response Evaluation Criteria in Solid Tumors (RECIST) of 30%.
* 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 4 of the first cycle of therapy for analysis of pharmacodynamic endpoints. Optional tumor biopsies may be requested at the completion of Course 1 (4 cycles) and in patients exhibiting objective responses.

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

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

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.

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.

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.

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.

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.

Studies on tumor tissue obtained during baseline /previous biopsy (if available), Cycle 1 Day 4(+/- 3 days), and possible treatment evaluation following Course 1.

National Cancer Institute (NCI)

Principal Investigator

Phase I Dose Level 1 Mithramycin 60 mcg/kg

Mithramycin: Phase 1: 24 hour intravenous infusion of mithramycin given once every 14 days at escalating doses..

Phase I Dose Level 1 Mithramycin 60 mcg/kg

Phase I Dose Level -1 Mithramycin 60 mcg/kg followed by Mithramycin 30 mcg/kg

Mithramycin: Phase 1: 24 hour intravenous infusion of mithramycin given once every 14 days at escalating doses.

Phase I Dose Level -1 Mithramycin 60 mcg/kg Followed by Mithramycin 30 mcg/kg

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. David S. Schrump

All participants in phase I dose level 1 and dose level -1.

All Participants

Maximum Tolerated Dose (MTD)

Complete Response

Partial Response

One participant in the first group only received one dose, thus was not evaluable.

Number of Participants Whose Best Response is a Complete Response (CR) or Partial Response (PR)

No data was collected thus this outcome measure was not done.

To Ascertain if Mithramycin Inhibits Stem Cell Gene Expression in Participants With Thoracic Malignancies

To Evaluate Gene Expression, Deoxyribonucleic Acid (DNA) Methylation and Micro-ribonucleic Acid (RNA) Profiles in Pre- and Post-treatment Tumor Biopsies

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

To Examine if Mithramycin Decreases Pluripotent Cancer Stem Cells (Side Population)

To Develop Methodologies for Assessing Effects of Mithramycin on Cancer Stem Cells, Hematopoietic Stem Cells, Mesenchymal Stem Cells, and Circulating Tumor Cells (CTC)

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

Number of Participants With a Dose-limiting Toxicity (DLT)

Overall Study

Spots Global Cancer Trial Database for abcb4 liver toxicity