Phase I Study on Doxil and SDZ PSC 833 in the Treatment of AIDS-Associated Kaposi's Sarcoma and Other Advanced Malignancies
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
- Safety profile and tolerability of Doxil in combination with PSC 833
研究概览
简要总结
The rationale for conducting this study lies in the premise that if indeed the reason for a limited response of Kaposi's sarcoma lesions and other advanced malignancies to chemotherapy is attributable to a high expression of P-glycoprotein, then, by inhibiting this pump, tumor kill would be enhanced and response rates as well as duration of responses would also increase. Doxil is chosen since recent studies have shown that it is superior to combination chemotherapy with ABV or BV. Doxil is also known to be active in other malignancies such as breast and ovarian cancer (34,35). PSC 833 is chosen since it has been found to reverse P-gp in vitro and in vivo, is non-immunosuppressive, and has been shown in recent Phase 1 studies to be well tolerated.
There are yet no human studies reported on Doxil pharmacokinetics when combined with MDR modulators. Preclinical data shows that pharmacokinetics of Doxil, unlike free doxorubicin, is minimally affected by the addition of PSC 833 (36). Enhanced tumor toxicity was observed when PSC 833 was combined with Doxil. Since doxorubicin, the active agent in Doxil, is metabolized by the same cytochrome P450, interactions between these 2 agents may have very significant clinical implications. The purpose of this study is to assess the toxicity and determine the maximum tolerated dose of Doxil when combined with PSC 833 in the treatment of AIDS-KS and other advanced malignancies.
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
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Phase 1 (Doxil & PSC 833)
Patients will receive Doxil at the standard dose of 20 mg/m2 IV for the 1st cycle. On the 2nd cycle of Doxil, the first patient will receive Doxil at 40% of standard dose or 8 mg/m2 (dose level 1) IV over one hr. 15 mn after the 2nd and subsequent cycles of Doxil, PSC 833 will be given at 2 mg/kg for 2 hrs. Simultaneously, a 72 hour CIVI of PSC 833 will be started with the loading dose. If no DLT occurs, then a double dose escalation of Doxil (dose levels 3, 5, 7 ) will be given to the same patient in the subsequent cycles until DLT occurs. On the 2nd cycle, Doxil will be given at the next dose level above the starting dose tolerated by the first patient. If no DLT occurs, a double dose escalation will also be done for the subsequent cycles (dose levels 5, 7, 9). The single-patient-cohort will terminate when a patient experiences DLT or when two episodes of grade 2 toxicity occur. At that point patients will be enrolled into cohorts of 3 patients to determine the MTD.
干预措施: pegylated liposomal doxorubicin hydrochloride (Drug)
Phase 1 (Doxil & PSC 833)
Patients will receive Doxil at the standard dose of 20 mg/m2 IV for the 1st cycle. On the 2nd cycle of Doxil, the first patient will receive Doxil at 40% of standard dose or 8 mg/m2 (dose level 1) IV over one hr. 15 mn after the 2nd and subsequent cycles of Doxil, PSC 833 will be given at 2 mg/kg for 2 hrs. Simultaneously, a 72 hour CIVI of PSC 833 will be started with the loading dose. If no DLT occurs, then a double dose escalation of Doxil (dose levels 3, 5, 7 ) will be given to the same patient in the subsequent cycles until DLT occurs. On the 2nd cycle, Doxil will be given at the next dose level above the starting dose tolerated by the first patient. If no DLT occurs, a double dose escalation will also be done for the subsequent cycles (dose levels 5, 7, 9). The single-patient-cohort will terminate when a patient experiences DLT or when two episodes of grade 2 toxicity occur. At that point patients will be enrolled into cohorts of 3 patients to determine the MTD.
干预措施: PSC 833 (Drug)
结局指标
主要结局
Safety profile and tolerability of Doxil in combination with PSC 833
Each cycle is 2 weeks long and can continue until disease progression, toxicity, or patient decision
Maximum tolerated dose of Doxil in combination with PSC 833
Dose limiting toxicity of Doxil in combination with PSC 833
次要结局
- Effects of PSC 833 on Doxil pharmacokinetics
- Confirm the MDR expression with immunohistochemistry and functionally, with 99MTc-sestamibi