Phase I Trial of Vorinostat (NSC-701852, Suberoylanilide Hydroxamic Acid) and Doxorubicin (NSC-123127, Adriamycin)
概览
- 阶段
- 1 期
- 干预措施
- doxorubicin hydrochloride
- 疾病 / 适应症
- Unspecified Adult Solid Tumor, Protocol Specific
- 发起方
- National Cancer Institute (NCI)
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Safety and tolerability as assessed by NCI CTCAE v3.0
- 状态
- 已完成
- 最后更新
- 12年前
概览
简要总结
This phase I trial is studying the side effects and best dose of vorinostat when given together with doxorubicin in treating patients with metastatic or locally 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 doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may help doxorubicin work better by making tumor cells more sensitive to the drug.
详细描述
PRIMARY OBJECTIVES: I. Determine the safety and tolerability of vorinostat (SAHA) and doxorubicin hydrochloride in patients with metastatic or locally advanced solid tumors. II. Determine the maximum tolerated dose of vorinostat when administered with doxorubicin hydrochloride in patients treated with this regimen. SECONDARY OBJECTIVES: I. Determine the response rate (complete response \[CR\] and partial response \[PR\]) and clinical benefits rate (CR, PR, and stable disease \> 12 weeks) in patients treated with this regimen. II. Determine the pharmacokinetics and pharmacodynamics of vorinostat and doxorubicin hydrochloride and their interaction. III. Determine the effects of vorinostat on histone acetylation in peripheral blood mononuclear cells and tumors. IV. Determine the effects of vorinostat on DNA damage induced by doxorubicin hydrochloride as a function of topoisomerase II expression. V. Determine the effects of vorinostat on genes and proteins crucial for the maintenance of chromatin structure. OUTLINE: This is a non-randomized, open-label, dose-escalation study of vorinostat. Patients receive oral vorinostat twice daily for 5 doses on days 1-3, 8-10, and 15-17 and doxorubicin hydrochloride IV on days 3, 10, and 17. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease after 6 courses of treatment may continue to receive vorinostat alone in the absence of disease progression. Cohorts of 3-6 patients receive escalating doses of vorinostat until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to15 patients are treated at the MTD. Mandatory biopsies are required in these patients. Patients undergo blood collection and tumor biopsies periodically during the study for pharmacologic, pharmacokinetic, pharmacodynamic, and biomarker correlative studies. After completion of study treatment, patients are followed for at least 30 days. PROJECTED ACCRUAL: A total of 40 patients will be accrued to this study.
研究者
入排标准
入选标准
- •Histologically or cytologically confirmed solid tumor malignancies for which no curative therapy exists
- •Measurable or evaluable disease with tumor that is accessible to biopsy as determined by CT scan or ultrasound
- •Skin, lymph nodes, or chest wall lesions are allowed provided measurements are confirmed by 2 independent health care professionals
- •No uncontrolled CNS metastases
- •Patients with stable CNS metastases (either surgically resected, treated with gamma knife, or stable for 3 months after whole-brain radiotherapy and documented by MRI within the past 4 weeks) are eligible
- •Willing to undergo pre- and post-vorinostat tumor biopsies
- •Life expectancy ≥ 3 months
- •ECOG performance status 0-2
- •WBC \> 3,000/mm\^3
- •Absolute neutrophil count \> 1,500/mm\^3
排除标准
- 未提供
研究组 & 干预措施
Treatment (vorinostat, doxorubicin hydrochloride)
Patients receive oral vorinostat twice daily for 5 doses on days 1-3, 8-10, and 15-17 and doxorubicin hydrochloride IV on days 3, 10, and 17. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease after 6 courses of treatment may continue to receive vorinostat alone in the absence of disease progression.
干预措施: doxorubicin hydrochloride
Treatment (vorinostat, doxorubicin hydrochloride)
Patients receive oral vorinostat twice daily for 5 doses on days 1-3, 8-10, and 15-17 and doxorubicin hydrochloride IV on days 3, 10, and 17. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease after 6 courses of treatment may continue to receive vorinostat alone in the absence of disease progression.
干预措施: vorinostat
Treatment (vorinostat, doxorubicin hydrochloride)
Patients receive oral vorinostat twice daily for 5 doses on days 1-3, 8-10, and 15-17 and doxorubicin hydrochloride IV on days 3, 10, and 17. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease after 6 courses of treatment may continue to receive vorinostat alone in the absence of disease progression.
干预措施: pharmacological study
Treatment (vorinostat, doxorubicin hydrochloride)
Patients receive oral vorinostat twice daily for 5 doses on days 1-3, 8-10, and 15-17 and doxorubicin hydrochloride IV on days 3, 10, and 17. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease after 6 courses of treatment may continue to receive vorinostat alone in the absence of disease progression.
干预措施: laboratory biomarker analysis
结局指标
主要结局
Safety and tolerability as assessed by NCI CTCAE v3.0
时间窗: Up to 30 days after completion of treatment
Maximum tolerated dose (MTD) of vorinostat as assessed by NCI CTCAE v3.0
时间窗: 28 days
次要结局
- Response rate (CR and PR) and clinical benefits rate (CR, PR, and stable disease) according to RECIST(Up to 30 days after completion of study treatment)
- Duration of response (overall response, complete response, and stable disease)(Up to 30 days after completion of study treatment)
- Correlation of dose and response with biological markers for histone acetylation, Topo II expression, assays for comet moments and expression patterns of chromatin structural proteins dose(Up to 30 days after completion of study treatment)
- Effects of vorinostat on histone acetylation(At baseline and at day 3 prior)