Phase I Pharmacokinetic Study of Belinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 72
- 试验地点
- 7
- 主要终点
- Dose Limiting Toxicity (DLTs)
研究概览
简要总结
Background:
- Belinostat is an experimental cancer treatment drug that works by helping to turn on genes that limit cell growth and survival of cancer cells. These genes are often switched off in tumors. Belinostat has been given to patients with different types of cancer to measure its safety and effectiveness, but it has not been given in a formal trial to cancer patients who have abnormal liver function. Because belinostat is processed by the liver, its safety and effectiveness needs to be established in individuals who have abnormal liver function. Researchers are interested in comparing the effects of belinostat as a cancer treatment drug in individuals with normal and abnormal liver function.
Objectives:
- To test the safety and effectiveness of belinostat in individuals who have solid tumors and lymphomas and who also have abnormal liver function.
- To compare the results of belinostat treatment in individuals with normal and abnormal liver function.
Eligibility:
- Individuals at least 18 years of age who have been diagnosed with solid tumors or lymphomas that have not responded to standard treatment.
- Individuals with normal liver function and varying degrees of abnormal liver function (mild, moderate, severe) are eligible.
Design:
- Participants will be screened with a full medical history and physical examination, as well as blood and urine tests, and tumor imaging studies. Participants will then be divided into study groups based on their liver function.
- Participants will receive belinostat in cycles of treatment. Except for cycle 1, all cycles will last 21 days. Cycle 1 will last 28 days. For cycle 1 only, participants will receive a single dose of belinostat 1 week before the regular 21-day treatment cycle starts.
- In each cycle, participants will receive belinostat once a day for 5 days, and will be asked to keep a medication diary to record any side effects.
- Participants will have regular clinic visits with blood and urine sample collection and imaging studies to evaluate the cancer's response to treatment.
- Participants may continue to take belinostat for as long as the cancer responds to the treatment.
详细描述
Background:
- Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs are frequently deregulated in cancer cells, leading to an increase in deacetylation and the silencing of genes that normally control cell cycle arrest and apoptosis.
- Belinostat has growth inhibitory activity in several malignancies in vitro and in vivo, both as a single agent and in combination with chemotherapeutic agents. Several Phase I and II clinical trials have been conducted to date in patients with solid tumor and hematologic malignancies; belinostat has been generally well tolerated.
- Belinostat is metabolized in the liver and therefore, the safety and dosing of belinostat needs to be established in patients with varying degrees of hepatic dysfunction.
Objectives:
- Establish the safety and tolerability of belinostat given on days 1 through 5 of 21-day cycles to patients with varying degrees of liver dysfunction.
- Define the maximum tolerated dose (MTD) and recommended dose of belinostat given on days 1 through 5 of 21-day cycles to patients with varying degrees of liver dysfunction.
- Evaluate the pharmacokinetics (PK) of one dose of belinostat (400 mg/m(2)) in patients with varying degrees of liver dysfunction.
- Obtain preliminary evidence of anti-tumor activity at tolerable doses of belinostat in patients with varying degrees of liver dysfunction.
- Measure direct versus indirect bilirubin levels and correlate these with observed toxicities, PK.
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 110 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
Normal Function-Belinostat 1000 mg/m(2)
Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN.
干预措施: Belinostat (Drug)
Mild Dysfunction-Belinostat 750 mg/m(2)
Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN.
干预措施: Belinostat (Drug)
Mild Dysfunction-Belinostat 1000 mg/m(2)
Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN.
干预措施: Belinostat (Drug)
Moderate Dysfunction-Belinostat 500 mg/m(2)
Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST).
干预措施: Belinostat (Drug)
Moderate Dysfunction-Belinostat 750 mg/m(2)
Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST).
干预措施: Belinostat (Drug)
Severe Dysfunction-Belinostat 250 mg/m(2)
Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST).
干预措施: Belinostat (Drug)
Severe Dysfunction-Belinostat 350 mg/m(2)
Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST).
干预措施: Belinostat (Drug)
结局指标
主要结局
Dose Limiting Toxicity (DLTs)
时间窗: First cycle of therapy, 28 days.
A DLT was defined as an adverse event deemed possibly, probably, or definitely related to administration of study drugs and met the following criteria: grade≥3 non-hematological toxicity (except grade ≥3 diarrhea, nausea, vomiting responsive to supportive therapy);grade≥3 rise in creatinine (except grade 3 able to be corrected to grade 1 or baseline with intravenous fluids within 24hrs); grade≥3 electrolyte toxicities (except those able to be corrected to grade 1 or baseline within 48hrs); grade 4 thrombocytopenia; grade 4 neutropenia for \>5 days or febrile neutropenia; any neurotoxicity grade≥2 not reversible to grade 1 or baseline within 2wks; or any delay in treatment by ≥2wks due to treatment-related toxicity. Worsening liver function, as defined by a rise in serum bilirubin not related to tumor progression, was considered a DLT if a patient with mild dysfunction became severe for 1wk, or if a patient in either the moderate/severe groups had a \>1.5x increase in bilirubin for 1 wk.
Maximum Tolerated Dose (MTD) of Belinostat According to Degree of Liver Dysfunction
时间窗: First cycle of therapy, 28 days
In order to maintain consistent dosing across the hepatic dysfunction groups, the dose recommended for cohorts with greater liver dysfunction could be no greater than the dose for cohorts of lesser dysfunction. In other words, it was assumed that a particular group would not tolerate a dose not tolerated by a group with lesser dysfunction and conversely, will tolerate a dose tolerated by a group with greater dysfunction. If a higher dose was tolerated in a group of greater dysfunction, but not in the group of lesser dysfunction, the lower dose would be recommended for both groups. The highest dose to be explored was no greater than the recommended dose for patients with normal liver function.
Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug
时间窗: From Cycle 1 Day -7 up to 12 (21-day) cycles
The number of participants experiencing each adverse event by liver function cohort at each dose level. The grade refers to the severity of the Adverse Event. Grade 1 Mild; Grade 2 Moderate; Grade 3 Severe or medically significant but not immediately life-threatening; Grade 4 Life-threatening consequences; Grade 5 Death related to adverse event.
Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax)
时间窗: Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.
Maximum plasma concentrations (Cmax) for belinostat and five metabolites on Cycle 1 Day -7 as a function of degree of liver dysfunction.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf)
时间窗: Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after start of infusion; and 5, 10, 15, 60, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.
Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf) for belinostat and four metabolites on Cycle 1 Day -7 as a function of degree of liver dysfunction.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf) of Belinostat
时间窗: Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.
Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf) for Belinostat glucuronide, a Belinostat Metabolite on Cycle 1 Day-7 as a function of degree of liver dysfunction.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2)
时间窗: Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.
Half-life Period (t1/2) of belinostat and five metabolites on Cycle 1 Day -7 as a function of degree of liver function.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Clearance (CL)
时间窗: Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.
Clearance (CL) of Belinostat on Cycle 1 Day-7 as a function of degree of liver dysfunction
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Volume of Distribution at Steady State (Vss)
时间窗: Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.
Belinostat Apparent volume of distribution at steady state (Vss) on Cycle 1 Day-7 as a function of degree of liver dysfunction.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Metabolic Ratios of Maximum Plasma Concentrations (Cmax) for the Belinostat Metabolic Pathway
时间窗: Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.
Metabolic ratios of Maximum Plasma Concentrations (Cmax), reported as a geometric mean (geometric standard deviation), for the belinostat metabolic pathway on Cycle 1 Day-7 as a function of degree of liver dysfunction.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Metabolic Ratios of Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf) for the Belinostat Metabolic Pathway
时间窗: Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.
Metabolic ratios of Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf), reported as geometric mean (geometric standard deviation), for the belinostat metabolic pathway on Cycle 1 Day-7 as a function of degree of liver dysfunction.
次要结局
- Best Response(at baseline and every two 21-day cycles of treatment, up to 12 cycles)
- Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0).(From Cycle 1 Day -7 up to 12 (21-day) cycles.)
研究者
Naoko Takebe, M.D.
Principal Investigator
National Cancer Institute (NCI)