Phase I Study of Ganetespib and Ziv-Aflibercept in Patients With Advanced Gastrointestinal Carcinomas, Non-Squamous Non-Small Cell Lung Carcinomas, Urothelial Carcinomas, and Sarcomas
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution Assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0
研究概览
简要总结
Background:
- Some people have cancers that don't respond to standard treatments. In these cases, doctors may try to use drugs to slow the growth of the cancer.
Objectives:
- To test the safety and efficacy of the drug combination of ganetespib and ziv-aflibercept.
Eligibility:
- Adults age 18 and over with advanced cancer of the colon, lung, urinary tract, and sarcomas.
Design:
- Participants will be screened with medical history, blood tests, and scans to measure their tumors.
- Participants will have one or two eye exams, with dilating eye drops.
- Participants will get the study drugs at the clinic as an infusion in a vein. Ganetespib will be given once a week on the same day for 3 weeks in a row, followed by a 1-week rest period. Ziv-aflibercept will be given once every other week. The drugs will be given in 28-day cycles.
- Participants may have a small piece of their tumor collected once or twice. This is done using a small needle during computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound scan.
- Participants will have their blood pressure checked at each visit. They will check it at home every day of the study.
- Participants may have one or more whole-body positron emission tomography (PET) scans with 89Zr-panitumumab. A small amount of a radioactive chemical will be injected through a tube in an arm. Participants will lie on a bed that slides in and out of the donut-shaped PET scanner. They will have small amounts of blood drawn.
- Participants may stay in the study as long as they are tolerating the drugs and their tumor is not getting worse.
详细描述
BACKGROUND:
- Ganetespib is a non-geldamycin synthetic inhibitor of Hsp90 that has demonstrated activity against multiple cancer cell lines and tumor xenografts in preclinical models. Inhibiting the Hsp90 chaperone complex results in the recruitment of ubiquitin ligases, polyubiquination, and proteosomal degradation of Hsp90 client proteins, including transcription factors and proteins involved in angiogenesis vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), hypoxia-inducible factor 1 (HIF-1), signal transducers and activators of transcription protein 3 (STAT-3); growth factor independence rapidly accelerated fibrosarcoma (RAF), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (Her2), insulin-like growth factor 1 receptor (IGFR); resistance to anti-growth signals cyclin-dependent kinase 4 (CDK4); tissue invasion and metastases mesenchymal-epithelial transition factor (MET), matrix metalloproteinase-2 (MMP2); and avoidance of apoptosis protein kinase B (AKT), rat insulin promoter (RIP), Survivin, B cell lymphoma (Bcl-2).
- HIF-1-alpha activation has been implicated in mediating resistance to anti-angiogenic therapy; recent evidence implicates a greater role for Hsp90 in direct modulation of VEGF signaling.
- Combining Hsp90 inhibition with ganetespib and anti-angiogenic therapy with Ziv-Aflibercept, a soluble fusion protein with high binding affinity for vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and placenta growth factor (PIGF), presents a rational novel strategy for improving upon and overcoming resistance to anti-angiogenic therapy
PRIMARY OBJECTIVE:
- To establish the safety, tolerability, and maximum tolerated dose (MTD) of the combination of ganetespib and Ziv-Aflibercept in patients with refractory gastrointestinal carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas
SECONDARY OBJECTIVE:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（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
Ganetespib and Ziv-Aflibercept
Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 + ziv-aflibercept at 3 mg/kg or 4 mg/kg.
干预措施: Ziv-Aflibercept (Drug)
Ganetespib and Ziv-Aflibercept
Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 + ziv-aflibercept at 3 mg/kg or 4 mg/kg.
干预措施: Ganetespib (Drug)
结局指标
主要结局
Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution Assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0
时间窗: Date treatment consent signed to date off study, approximately 12 months and 44 days
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.
Number of Participants With Grade 2 or Greater Adverse Events Possibly, Probably, or Definitely Related to Administration of the Study Drugs
时间窗: Date treatment consent signed to date off study, approximately 12 months and 44 days
Adverse Events were graded according to Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the Adverse Event. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event (AE). AEs were considered possibly attributable to both study drugs, except where otherwise noted. Star (\*) symbol indicates that the AE is possibly related to Ziv-aflibercept and unlikely to be related to Ganetespib.
Maximum Tolerated Dose (MTD) of the Combination of Ganetespib and Ziv-aflibercept
时间窗: Cycle one (28 days)
MTD is defined as the dose level at which no more than 1 of 6 patients experience a dose limiting toxicity (DLT) during the first cycle of the treatment, and the dose level below that at which at least 2 (of \<6) patients have a DLT as a result of the drug. Determination of DLT is based on the first cycle of treatment.
次要结局
- Modulation of Hypoxia-Inducible Factor 1 (HIF-1) Alpha(Cycle 2, Day 7)
- Modulation of Epidermal Growth Factor Receptor (EGFR) Expression(Cycle 1 Day 16)
- Number of Participants According to Best Response Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1)(Baseline and every 2 months up to 5 months)
- Number of Cycles on Treatment(up to 5 months)
研究者
Alice Chen, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)