Vorinostat and Carboplatin or Vorinostat and Paclitaxel in Patients With Advanced Solid Tumors: A Pharmacokinetic and Pharmacodynamic Study
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Peak concentrations (Cmax) of vorinostat at 400, 1200, and 1600 mg
研究概览
简要总结
This randomized pilot clinical trial studies high-dose or low-dose vorinostat in combination with carboplatin or paclitaxel in treating patients with advanced solid tumors. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving different doses of vorinostat together with carboplatin or paclitaxel may kill more tumor cells.
详细描述
PRIMARY OBJECTIVES:
I. To determine whether high dose, short course vorinostat achieves higher peak serum concentrations than standard dosing.
SECONDARY OBJECTIVES:
I. To determine the toxicity profiles of two different escalated intermittent dosing schedules of vorinostat combined with carboplatin at an area under curve (AUC) of 5.
II. To describe the response rate in patients with advanced solid tumors treated with these regimens.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which no superior curative or palliative measures are known
- •At least 4 weeks must have passed since prior chemotherapy or radiation therapy; 6 weeks if the last regimen included BCNU or mitomycin C
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •Life expectancy of greater than 3 months
- •Leukocytes > 3,000/mcL
- •Absolute neutrophil count > 1,500/mcL
- •Platelets > 100,000/mcL
- •Total bilirubin < institutional upper limits of normal
- •Potassium < institutional upper limits of normal
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal, or < 5 x ULN if liver metastases are present
- •Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- •Ability to understand and the willingness to sign a written informed consent document
排除标准
- •Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier (except alopecia, lymphopenia, hyperglycemia, hypoalbuminemia and elevated serum alkaline phosphatase); all other toxicities should have resolved to grade 1 or less prior to beginning treatment
- •Patients may not be receiving any other investigational agents
- •Patients with known brain metastases that are untreated or have progressed after definitive therapy should be excluded from this clinical trial; patients with treated brain metastases, who are no longer receiving steroids for at least 14 days, are not receiving enzyme-inducing anti-epileptic drugs, and have no unstable neurologic symptoms may be enrolled at the discretion and joint decision of the principal investigator and treating physician
- •Prior or current use of valproic acid, a histone deacetylase (HDAC) inhibitor
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel, vorinostat or carboplatin
- •Inability to swallow oral medications
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Women that are pregnant or breastfeeding are excluded from this study; all women of child-bearing potential must have a negative pregnancy test before receiving vorinostat; women of child-bearing potential and men must agree to use adequate contraception for the duration of the study; breastfeeding should be discontinued if the mother is treated with vorinostat; these potential risks may also apply to other agents used in this study; subjects that become pregnant or think they may be pregnant while taking part in this study should notify their treating physician immediately
- •Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
研究组 & 干预措施
Arm I (high- and low-dose vorinostat and carboplatin)
Patients receive high-dose vorinostat PO QD on days 1-3 and low-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive high-dose vorinostat PO QD on days 1-3 and carboplatin IV over 30 minutes on day 3 of all subsequent courses.
干预措施: Carboplatin (Drug)
Arm I (high- and low-dose vorinostat and carboplatin)
Patients receive high-dose vorinostat PO QD on days 1-3 and low-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive high-dose vorinostat PO QD on days 1-3 and carboplatin IV over 30 minutes on day 3 of all subsequent courses.
干预措施: Vorinostat (Drug)
Arm II (high- and low-dose vorinostat and carboplatin)
Patients receive high-dose vorinostat and low-dose vorinostat as in Arm I. After 5 days, patients receive lower-dose vorinostat PO QD on days 1-3 and carboplatin IV over 30 minutes on day 3.
干预措施: Carboplatin (Drug)
Arm II (high- and low-dose vorinostat and carboplatin)
Patients receive high-dose vorinostat and low-dose vorinostat as in Arm I. After 5 days, patients receive lower-dose vorinostat PO QD on days 1-3 and carboplatin IV over 30 minutes on day 3.
干预措施: Vorinostat (Drug)
Arm III (low- and high-dose vorinostat and carboplatin)
Patients receive low-dose vorinostat PO QD on days 1-3 and high-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive vorinostat and carboplatin as in Arm I.
干预措施: Carboplatin (Drug)
Arm III (low- and high-dose vorinostat and carboplatin)
Patients receive low-dose vorinostat PO QD on days 1-3 and high-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive vorinostat and carboplatin as in Arm I.
干预措施: Vorinostat (Drug)
Arm IV (low- and high-dose vorinostat and carboplatin)
Patients receive low-dose vorinostat and high-dose vorinostat as in Arm III. After 5 days, patients receive vorinostat and carboplatin as in Arm II.
干预措施: Carboplatin (Drug)
Arm IV (low- and high-dose vorinostat and carboplatin)
Patients receive low-dose vorinostat and high-dose vorinostat as in Arm III. After 5 days, patients receive vorinostat and carboplatin as in Arm II.
干预措施: Vorinostat (Drug)
Arm V (low- and mid-dose vorinostat and paclitaxel)
Patients receive low-dose vorinostat PO QD on days 1-3 and mid-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive mid-dose vorinostat PO QD on days 1-3 and paclitaxel IV over 3 hours on day 3.
干预措施: Paclitaxel (Drug)
Arm V (low- and mid-dose vorinostat and paclitaxel)
Patients receive low-dose vorinostat PO QD on days 1-3 and mid-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive mid-dose vorinostat PO QD on days 1-3 and paclitaxel IV over 3 hours on day 3.
干预措施: Vorinostat (Drug)
Arm VI (mid- and low-dose vorinostat and paclitaxel)
Patients receive mid-dose vorinostat PO QD on days 1-3 and low-dose vorinostat PO QD on days 8-10. After 5 days, patients receive vorinostat and paclitaxel as in Arm V.
干预措施: Paclitaxel (Drug)
Arm III (low- and high-dose vorinostat and carboplatin)
Patients receive low-dose vorinostat PO QD on days 1-3 and high-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive vorinostat and carboplatin as in Arm I.
干预措施: Pharmacological Study (Other)
Arm V (low- and mid-dose vorinostat and paclitaxel)
Patients receive low-dose vorinostat PO QD on days 1-3 and mid-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive mid-dose vorinostat PO QD on days 1-3 and paclitaxel IV over 3 hours on day 3.
干预措施: Pharmacological Study (Other)
Arm I (high- and low-dose vorinostat and carboplatin)
Patients receive high-dose vorinostat PO QD on days 1-3 and low-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive high-dose vorinostat PO QD on days 1-3 and carboplatin IV over 30 minutes on day 3 of all subsequent courses.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (high- and low-dose vorinostat and carboplatin)
Patients receive high-dose vorinostat PO QD on days 1-3 and low-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive high-dose vorinostat PO QD on days 1-3 and carboplatin IV over 30 minutes on day 3 of all subsequent courses.
干预措施: Pharmacological Study (Other)
Arm II (high- and low-dose vorinostat and carboplatin)
Patients receive high-dose vorinostat and low-dose vorinostat as in Arm I. After 5 days, patients receive lower-dose vorinostat PO QD on days 1-3 and carboplatin IV over 30 minutes on day 3.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (high- and low-dose vorinostat and carboplatin)
Patients receive high-dose vorinostat and low-dose vorinostat as in Arm I. After 5 days, patients receive lower-dose vorinostat PO QD on days 1-3 and carboplatin IV over 30 minutes on day 3.
干预措施: Pharmacological Study (Other)
Arm III (low- and high-dose vorinostat and carboplatin)
Patients receive low-dose vorinostat PO QD on days 1-3 and high-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive vorinostat and carboplatin as in Arm I.
干预措施: Laboratory Biomarker Analysis (Other)
Arm IV (low- and high-dose vorinostat and carboplatin)
Patients receive low-dose vorinostat and high-dose vorinostat as in Arm III. After 5 days, patients receive vorinostat and carboplatin as in Arm II.
干预措施: Laboratory Biomarker Analysis (Other)
Arm IV (low- and high-dose vorinostat and carboplatin)
Patients receive low-dose vorinostat and high-dose vorinostat as in Arm III. After 5 days, patients receive vorinostat and carboplatin as in Arm II.
干预措施: Pharmacological Study (Other)
Arm V (low- and mid-dose vorinostat and paclitaxel)
Patients receive low-dose vorinostat PO QD on days 1-3 and mid-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive mid-dose vorinostat PO QD on days 1-3 and paclitaxel IV over 3 hours on day 3.
干预措施: Laboratory Biomarker Analysis (Other)
Arm VI (mid- and low-dose vorinostat and paclitaxel)
Patients receive mid-dose vorinostat PO QD on days 1-3 and low-dose vorinostat PO QD on days 8-10. After 5 days, patients receive vorinostat and paclitaxel as in Arm V.
干预措施: Laboratory Biomarker Analysis (Other)
Arm VI (mid- and low-dose vorinostat and paclitaxel)
Patients receive mid-dose vorinostat PO QD on days 1-3 and low-dose vorinostat PO QD on days 8-10. After 5 days, patients receive vorinostat and paclitaxel as in Arm V.
干预措施: Pharmacological Study (Other)
Arm VI (mid- and low-dose vorinostat and paclitaxel)
Patients receive mid-dose vorinostat PO QD on days 1-3 and low-dose vorinostat PO QD on days 8-10. After 5 days, patients receive vorinostat and paclitaxel as in Arm V.
干预措施: Vorinostat (Drug)
结局指标
主要结局
Peak concentrations (Cmax) of vorinostat at 400, 1200, and 1600 mg
时间窗: 0 (pre-treatment), 60, 120, 180, 240, 360 and 480 minutes and 24 hours after vorinostat administration on days 3 and 10 of course 0 and on day 3 of course 1
次要结局
- Adverse events of two different escalated intermittent dosing schedules of vorinostat combined with carboplatin as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0(Up to 4 weeks)
- Pharmacodynamic markers of vorinostat activity, including AUC and changes in platelet counts(0 (pre-treatment), 60, 120, 180, 240, 360 and 480 minutes and 24 hours after vorinostat administration on days 3 and 10 of course 0 and on day 3 of course 1)