Phase I Study of Radiation Therapy With Concurrent Sorafenib for Hepatocellular Carcinoma Not Responding to Transarterial Chemoembolization
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose
研究概览
简要总结
To determine the maximum tolerated radiation dose with concurrent sorafenib for unresectable hepatocellular carcinoma that has not responded to transarterial chemoembolization.
详细描述
In patients with unresectable hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) is first line therapy. Non-responders to TACE (i.e. stable or progressive disease) represent a poor prognosis population with limited options. Sorafenib is indicated for first line salvage therapy, however it only improves survival 2-3 months and just has a 2-3% response rate. Thus, sorafenib is merely a cytostatic agent that delays progression and does not cytoreduce disease.
Radiation therapy (RT) is a non-invasive treatment that can cytoreduce HCC with minimal morbidity using modern techniques. A meta-analysis and multiple retrospective series suggest TACE + RT improve survival when compared to TACE alone. Higher RT doses are similarly associated with increased survival due to improved local control. Paradoxically, some series suggest that RT can induce vascular endothelial growth factor (VEGF) expression which may stimulate HCC.
Pre-clinical data suggest that combining RT with concurrent sorafenib (a VEGF inhibitor) improves tumor control. However, clinical data is limited to case reports and safety has not been well characterized. Prior to determining if this combination can improve control of HCC in this poor prognosis population, the optimal radiation dose with concurrent sorafenib must be determined by a phase I dose escalation trial.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Radiographic or histologic diagnosis of hepatocellular carcinoma (HCC).
- •Maximum of 3 HCC lesions within the liver.
- •No evidence of lymphadenopathy or metastatic disease per either CT or PET.
- •Prior transarterial chemo-embolization (TACE) at least 28 days prior to initiation of protocol therapy.
- •Evidence of either progressive disease or stable disease following TACE.
- •Child Pugh Class A (score 5-6) or B (score 7).
- •Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 (or Karnofsky ≥70%).
- •Normal organ and marrow function (platelets >60,000/mc; hemoglobin ≥8.5 g/dL; international normalized ratio (INR) ≤2.3; albumin ≥2.8 g/dL; total bilirubin ≤3 mg/dL; aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <5x upper limit of normal; creatinine ≤1.5x upper limit of normal).
- •Negative human immunodeficiency virus serology.
- •Negative pregnancy test for women of child bearing age.
- •Ability to understand and willingness to sign a written informed consent document.
排除标准
- •Less than 800 cc of normal liver.
- •Child Pugh Class B (score 8-9) or C (score 10-15).
- •Acute/active hepatitis B infection.
- •Prior systemic chemotherapy or abdominal radiation therapy.
- •Portal venous (main, primary right, or primary left trunks) or inferior vena cava thrombosis.
- •Prior malignancy within 5 years of enrollment except for non-melanoma skin cancer.
- •Prior history of myocardial infarction, cerebrovascular accident, or esophageal variceal bleed in the last 6 months.
- •Pre-existing heart failure with either a clinical classification of New York Heart Association Class III or IV or cardiac ejection fraction of <45%.
- •Systolic blood pressure > 160 mmHg or diastolic pressure > 100 mmHg despite optimal medical management.
- •Pulmonary hemorrhage or other serious bleeding event (grade 2+) within 4 weeks initiation of protocol therapy.
- •Prior history of scleroderma or active systemic lupus erythematosus.
研究组 & 干预措施
Radiation therapy with concurrent sorafenib
干预措施: Sorafenib (Drug)
Radiation therapy with concurrent sorafenib
干预措施: Conventional fractionation (2 Gy per day) external beam radiation therapy (Radiation)
结局指标
主要结局
Maximum Tolerated Dose
时间窗: From date of enrollment until 3 months after completion of treatment.
Maximum tolerated dose (MTD) will be determined by dose limiting toxicity (DLT) that is observed in either the acute (during treatment) or subacute (up to 3 months after treatment) setting. Acute DLT will be defined by grade 3-5 hepatic, gastrointestinal, dermatologic, hematologic, or pulmonary toxicity per Common Toxicity Criteria for Adverse Effects (CTCAE), v4.0. Subacute DLT will be defined by radiation induced liver disease (RILD) or grade 3-5 gastrointestinal, hematologic, or pulmonary toxicity per CTCAE, v4.0.
次要结局
- Radiographic Response(1 & 3 months post-treatment.)
- Patterns of Failure(From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years.)
- Progression Free Survival(From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years.)
- Overall Survival(From date of enrollment until the date of last known folow-up or date of death from any cause, whichever came first, assessed up to 10 years.)
- Health Related Quality of Life(1, 2, & 3 months post-treatment.)