A Phase I/II Study of TRC105 in Combination With Sorafenib in Hepatocellular Carcinoma (HCC)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 27
- 试验地点
- 1
- 主要终点
- Phase I: Maximum Tolerated Dose (MTD) of TRC105 When Given With Standard-dose Sorafenib for Hepatocellular Cancer (HCC)
研究概览
简要总结
Background:
Sorafenib is a drug that has been approved to treat kidney and liver cancer (hepatocellular carcinoma, or HCC) and has been shown to prolong survival in patients with HCC. It works by slowing the spread of cancer cells, but it does not fully prevent the cancer from growing again. Researchers are interested in combining sorafenib with the experimental drug TRC105, which has been designed to block the growth of blood vessels that lead to tumor growth, in order to determine whether this drug combination stops tumor growth and reduces tumor size better than sorafenib alone.
Objectives:
To determine the safety and effectiveness of the combination of sorafenib and TRC105 as a treatment for hepatocellular cancer that has not responded to other treatments.
Eligibility:
Individuals at least 18 years of age who have been diagnosed with hepatocellular cancer that has not responded to other treatments, and who are not considered to be candidates for liver transplantation. Patients cannot be receiving anticoagulant therapy with the exception of low dose aspirin. No history of bleeding problems or peptic ulcer disease.
Design:
Participants will be screened with a full medical history and physical examination, blood and urine tests, and tumor imaging studies. Participants will have a tumor biopsy or provide previously collected tumor tissue for study. An examination of the esophagus to look for problems with blood vessels will be completed in patients with a history of cirrhosis.
Participants will receive sorafenib tablets twice every day, in the morning and at night, with a full glass of water.
Participants will receive TRC 105 infusions once every two weeks on days 1 and 15 of a 28 day cycle.
At each visit during the first cycle, participants will have a physical examination and blood tests. Participants will continue to have blood tests and a urine test every cycle to monitor the effects of treatment, including tests of kidney function. Participants will have imaging studies after every two cycles to evaluate the results of treatment, and may also provide tumor samples for study.
Treatment will continue as long as the tumor does not grow and side effects remain tolerable.
详细描述
Background:
- Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a median survival of 6-9 months. The Study of Heart and Renal Protection (SHARP) study established sorafenib as a standard consideration in this disease and set the bar for future studies of systemic therapy.
- TRC105 is a chimeric anti-angiogenic monoclonal antibody that binds cluster of differentiation 105 (CD105), a transmembrane receptor selectively expressed by proliferating endothelial cells. TRC105 binds to CD105-expressing endothelial cells and mediates growth inhibition, apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC).
Objectives:
Primary:
- Phase I: To establish the maximum tolerated dose (MTD) of TRC105 when given with standard-dose sorafenib for HCC.
- Phase II:To determine the estimate response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria for the combination of TRC105 with sorafenib in HCC.
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 99 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
Sorafenib & TRC105 in Hepatocellular CA
CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day
干预措施: TRC 105 (Drug)
Sorafenib & TRC105 in Hepatocellular CA
CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day
干预措施: Sorafenib (Drug)
结局指标
主要结局
Phase I: Maximum Tolerated Dose (MTD) of TRC105 When Given With Standard-dose Sorafenib for Hepatocellular Cancer (HCC)
时间窗: Completed in the first 28 days of treatment (cycle 1)
MTD is the highest dose studied for which the incidence of DLT was less than 33%. DLT criteria included treatment-related grade 3 non-hematological toxicities or grade 4 hematological toxicities occurring within the first 28 days of treatment. Grade 3 electrolyte toxicities to be corrected to Grade 1 or less within 24 hours will be considered dose limiting (proteinuria \>3.5g/24 hour will be defined as a DLT). Drug-related Grade 4 hematological toxicity will be considered dose limiting. Toxicity requiring a dose reduction or a delay in treatment for \>7 days will be considered dose limiting. Other Grade 3 or higher toxicity related to TRC105 will be considered dose limiting.
Phase II: Time to Progression (TTP) for the Combination of TR105 With Sorafenib in Hepatocellular Cancer (HCC)
时间窗: 2 years
TTP is the time between the first day of treatment to the day of disease progression. Progressive disease was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions, 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).
次要结局
- Overall Response Rate (ORR) as Determined by the Standard Response Evaluation Criteria in Solid Tumors (RECIST) Criteria(2 years)
- Overall Response Rate (ORR) as Determined by the European Association for the Study of the Liver (EASL)-Modified Response Evaluation Criteria in Solid Tumors (RECIST) Criteria(2 years)
- Number of Participants With Serious and Non-serious Adverse Events by Common Terminology Criteria in Adverse Events (CTCAE)v4.0(4 years and 10.5 months)
- Area Under the Plasma Concentration(Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, and prior to start of TRC105 infusion)
- Patients Who Developed Antidrug Antibodies(Cycle 1 Day 1, 28 days post end of study (up to 2 years))
- Immunogenicity of TRC105 as Measured by Human Anti-mouse Antibody (HAMA) Formation(Baseline and then 28 days following the end of the study treatment, approximately two years)
- Number of Participants With Dose Limiting Toxicity (DLT)(First 28 days of treatment (cycle 1))
- Treatment-emergent Adverse Events(4 years and 10.5 months)
- Median Progression-free Survival (PFS)(up to 6 months)
- Percentage of Participants With Progression Free Survival (PFS) at 3 and 6 Months(3 and 6 months)
- Median Overall Survival (OS)(up to 2 years)
- Percentage of Participants With Overall Survival (OS) at 6 and 12 Months(6 and 12 months)
- Changes in Biomarkers Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PIGF)(Cycle 1 day 1, cycle 1 day 15, cycle 2 day 1, or end of study, an average of 12 weeks)
- Number of Participants With Stable Disease, Partial Response, and Progressive Disease on Phase I and Phase II of the Clinical Trial(Every 8 weeks, up to 180 days)
- Changes in Biomarker Cluster of Differentiation 105 (CD105)(Cycle 1 day 1, cycle 1 day 15, cycle 2 day 1, or end of study (eos), an average of 12 weeks)
- Percentage Signal Change in Response on Magnetic Resonance Imaging (MRI)(Baseline and Cycle 1 Day 2 and Cycle 2 Day 1, an average of 12 weeks)
研究者
Tim Greten, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)