Treatment of Unresectable Hepatocellular Cancer With Opioid Growth Factor: a Phase I Study
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 14
- 试验地点
- 1
- 主要终点
- Number of participants with opioid growth factor toxicity
研究概览
简要总结
Hepatocellular cancer, one of the world's most deadly tumors, is associated with chronic liver injury and cirrhosis. With the increasing occurrence of viral hepatitis, the incidence of this cancer in the United States continues to rise. Surgical resection offers the only hope for cure; but sadly, few patients are candidates for surgery due to their liver disease. Liver transplant can be an effective treatment, but due to a scarcity of organs, most patients do not qualify for this therapy either. Patients who are not candidates for these procedures have very few therapeutic options as chemotherapy and radiation have little efficacy. New therapies are desperately needed.
Opioid Growth Factor (OGF) inhibits the growth of a number of cancer lines in vitro by a receptor-mediated mechanism. In pancreatic cancer this phenomenon has been well defined not only in vitro but in animal models. Based upon these findings, a phase I trial has been conducted demonstrating that OGF can be administered safely to patients with pancreatic cancer. The investigators hypothesize that administration of OGF will inhibit the course of cancer progression in human subjects with unresectable hepatocellular cancer and cirrhosis. As a first step in testing this hypothesis, the investigators propose a phase I trial to study the toxicity and pharmacokinetics of this therapy in patients suffering from inoperable hepatocellular cancer and cirrhosis.
详细描述
STUDY OBJECTIVES Hepatocellular cancer (HCC) is one of the most prevalent cancers in the world. About 19,160 new cases are anticipated to occur in the US in 2007. Any form of chronic liver injury and cirrhosis predisposes to the development of this malignancy. Worldwide, the most common risk factor is viral hepatitis; in the United States other sources of chronic liver injury such as cirrhosis related to alcohol use are important, but the incidence of viral hepatitis continues to increase. Regardless of the etiology, the only known cure for HCC is surgical resection. Unfortunately, due to associated liver disease and stage of tumor progression at the time of diagnosis, very few patients are candidates for surgical therapy. Chemotherapy has shown very little efficacy in this disease, and radiation is of little value due to associated liver toxicity. New therapies are desperately needed.
Research examining the mechanisms involved in the growth of human cancer has shown that the peptide [Met5]-enkephalin, Opioid Growth Factor (OGF), inhibits growth of a number of cancer lines in vitro. In pancreatic cancer this phenomenon has been well defined not only in vitro but in vivo after transfer of human tumors into nude mice. The suppressive effect on growth by this peptide is by a receptor-mediated mechanism. Based upon these findings, a phase I trial has been conducted studying the effects of OGF in patients with pancreatic cancer. We hypothesize that administration of OGF will inhibit the course of carcinogenic events in human subjects with unresectable hepatocellular cancer and cirrhosis. In order to test this hypothesis we propose a phase I trial to study the toxicity of this therapy in patients suffering from liver disease and cirrhosis addressing the following specific aims:
Specific Aim 1: Determine the maximum-tolerated dose (MTD) of OGF after an intravenous infusion in patients suffering from HCC. While the MTD has been determined for patients suffering from pancreatic cancer, it is unclear that these results will hold true in patients with HCC who suffer from liver insufficiency and cirrhosis. For this reason we will conduct a dose-finding trial that contains dose-escalation of OGF. Dose-limiting toxicities will be determined by monitoring liver function, pupillary size & response, respiration, vital signs (orthostatic blood pressure and pulse), gastrointestinal distress, cutaneous flushing, and effects on blood count, glucose and electrolytes.
Specific Aim 2: Study the pharmacokinetics and metabolism of OGF in patients with HCC and cirrhosis by monitoring plasma OGF levels. Blood samples will be collected prior to and at designated intervals after an infusion of the MTD of OGF in cancer patients. OGF plasma levels will be analyzed by performing radioimmunoassay.
The long-term objectives of our research team are to understand the effects of peptide growth factors in patients with HCC and cirrhosis. This phase I trial will be useful in determining the appropriate dose and expected toxicities of OGF in these patients. Our study employs the use of a naturally occurring opioid peptide, which has been shown to inhibit growth of pancreatic cancer in preclinical studies, and to be safely administered to patients with pancreatic cancer.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •In this acute dose-finding section of the study, we will enroll patients with HCC and cirrhosis.
- •Both male and female patients 18 years of age or older will be eligible.
- •Patients with cancer must have a Karnofsky performance rating of at least 50%.
- •Patients must have HCC and cirrhosis that is not amenable to current therapies including liver resection, tumor ablation, or liver transplant.
- •Patients must be mentally alert and able to give informed consent.
- •Female patients who are menopausal, or of childbearing age who are surgically sterile or practicing birth control (chemical or mechanical) are eligible.
- •All females of childbearing potential must have a serum pregnancy test upon entry into the study and must take precautions to not become pregnant during the study (from the time of enrollment until 1 week after the infusion of OGF). No corticosteroid or narcotic therapy 24 hrs prior to infusion.
- •Volunteers must refrain from alcoholic beverages for 24 hours before, and 24 hours after, the day of infusion.
- •If patients have received sorafenib, at least 4 weeks must pass from the last dose.
- •At least four weeks must pass from significant surgery and the subject must be physically recovered.
排除标准
- •Patients with asthma, chronic obstructive pulmonary disease, unstable cardiovascular diseases (congestive heart failure, symptoms of coronary artery disease, cardiac arrhythmias, poorly controlled hypertension, have suffered a myocardial infarction in the preceding year or have an abnormal EKG) will not be allowed.
- •Patients with poorly controlled diabetes, seizure disorders, primary central nervous system (CNS) tumors or known brain metastases are excluded.
- •A clinical judgment will be made based on the other criteria and performance status as to the patient's ability to tolerate therapy.
- •Serum total bilirubin and international normalized ratio (INR) will be used as markers of liver function in the exclusion criteria as defined in Table 1 (see below).
- •Pregnant or nursing women are not eligible.
- •Patients requiring antibiotics in the preceding week for a serious infection are not eligible.
- •Volunteers may have on the morning of the study one 8 ounce glass of water or juice and toast.
- •EKG and laboratory tests will be reviewed to evaluate whether any exclusion criteria are met.
- •Those who are not eligible will be notified.
- •Table 1: Exclusion Criteria
- •Leukocyte Count < 3500/μl
- •Hemoglobin < 8500/μl
- •Blood urea nitrogen (BUN) > 30mg/dl (hydrated)
- •Creatinine > 2 mg/dl
- •Platlet Count < 55,000/mm3
- •INR (unless on coumadin) > 2
- •Total Bilirubin > 3.5mg/dl
- •Sodium < 130 mmol/L
- •Potassium <3.2 mmol/L
- •Glucose > 300 or < 60 mg/dl
研究组 & 干预措施
Infusion of opioid growth factor
Volunteers will be treated with an intravenous infusion of opioid growth factor(OGF) starting at 100 µg/kg with a 50 µg/kg dose escalation with each succeeding group. The investigational drug, OGF, will be diluted in sterile saline to its appropriate concentration based upon the body weight of the volunteer and administered in a volume of 60 ml over 45 minutes (rate of 2 ml/min)
干预措施: Infusion of opioid growth factor (Drug)
结局指标
主要结局
Number of participants with opioid growth factor toxicity
时间窗: Over the period of infusion and 1 hour after infusion
primary outcome variable is toxicity and or tolerance to opioid growth factor in patients with hepatocellular cancer
次要结局
- Change in plasma opioid growth factor levels(During the infusion and 1 hour after infusion)
研究者
Eric Kimchi
Associate Professor of Surgical Oncology
University of Missouri-Columbia