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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Phase I/Escalating doses of Mithramycin
Escalating doses of Mithramycin
干预措施: Mithramycin (Drug)
Phase II/Mithramycin administered at Maximum Tolerated Dose (MTD)
Mithramycin administered at MTD
干预措施: Mithramycin (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: 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.
Number of Participants Whose Best Response is a Complete Response (CR) or Partial Response (PR)
时间窗: 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.
次要结局
- To Ascertain if Mithramycin Inhibits Stem Cell Gene Expression in Participants With Thoracic Malignancies(baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1)
- To Evaluate Gene Expression, Deoxyribonucleic Acid (DNA) Methylation and Micro-ribonucleic Acid (RNA) Profiles in Pre- and Post-treatment Tumor Biopsies(baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1)
- 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(baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1)
- To Examine if Mithramycin Decreases Pluripotent Cancer Stem Cells (Side Population)(baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1)
- To Develop Methodologies for Assessing Effects of Mithramycin on Cancer Stem Cells, Hematopoietic Stem Cells, Mesenchymal Stem Cells, and Circulating Tumor Cells (CTC)(baseline, Cycle 1 Day 4 (+/- 3 days), and possible treatment evaluation following Course 1)
研究者
David Schrump, M.D.
Principal Investigator
National Cancer Institute (NCI)