A Phase I Trial of Sirolimus (mTOR Inhibitor) or Vorinostat (HDAC Inhibitor) in Combination With Hydroxychloroquine (Autophagy Inhibitor) in Patients With Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 143
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of Sirolimus or Vorinostat in Combination with Hydroxychloroquine in Participants with Advanced Cancers
研究概览
简要总结
The goal of this clinical research study is to find the highest tolerable dose of sirolimus or vorinostat that can be given in combination with hydroxychloroquine to patients with advanced cancer. The safety of these drug combinations will also be studied.
详细描述
Study Drug Dose Level:
If you are found to be eligible to take part in this study, you will be assigned to a dose level of hydroxychloroquine and either sirolimus or vorinostat, based on when you joined this study, availability of spots for each drug combination, and what your doctor thinks is in your best interest. Up to 11 dose levels of the sirolimus and hydroxychloroquine combination and 7 dose levels of the vorinostat and hydroxychloroquine combination will be tested. Three (3) to 6 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level of the study drug combination. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of each drug combination is found.
Once the highest tolerated dose of each drug combination is found, up to 28 more participants (14 per combination) will be given this dose. The study doctor will decide which drug combination each participant is given, based on their tumor type.
Study Drug Administration:
Each study "cycle" is 21 days.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Patients with advanced or metastatic cancers that are refractory to standard therapy, relapsed after standard therapy, or who have no standard therapy available that improves survival by at least three months.
- •Patients must be >/= 18 years.
- •Patients must be >/= 3 weeks beyond treatment with a cytotoxic chemotherapy regimen, or therapeutic radiation, or major surgery. Patients may have received palliative localized radiation immediately before or during treatment provided that radiation is not delivered to the only site of disease being treated under this protocol. For biologic/targeted agents patients must be >/= 5 half-lives or >/= 3 weeks form the last dose (whichever comes first).
- •ECOG performance status </= 2
- •Patients must have adequate organ and marrow function defined as: absolute neutrophil count >/= 1,000/mL;platelets >/=50,000/mL; creatinine </= 2 X ULN; total bilirubin </= 2.0 (exceptions may apply to benign non-malignant indirect hyperbilirubinemia such as Gilbert syndrome); ALT(SGPT) </= 5 X ULN; Exception for patients with liver metastasis: total bilirubin </= 3 x ULN; ALT(SGPT) </= 8 X ULN;cholesterol </= 350 mg/dL; triglycerides </= 400 mg/dL (sirolimus and hydroxychloroquine only).
- •Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days after the last dose.
- •Patients must be able to understand and be willing to sign a written informed consent document.
排除标准
- •Uncontrolled intercurrent illness, including, but not limited to, uncontrolled infection, uncontrolled asthma, need for hemodialysis, need for ventilatory support.
- •Pregnant or lactating women.
- •History of hypersensitivity to sirolimus.
- •History of hypersensitivity to vorinostat
- •History of hypersensitivity to hydroxychloroquine
- •History of hypersensitivity to any component of the formulation.
- •Patients unwilling or unable to sign informed consent document.
- •Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
- •Patients with known glucose-6-phosphate dehydrogenase deficiency.
- •Patients with porphyria cutanea tarda.
- •Patients with psoriasis.
- •Patients with pre-existing maculopathy or retinopathy of the eye.
- •Patients who have a pre-existing myopathy.
研究组 & 干预措施
Hydroxychloroquine + Sirolimus
Hydroxychloroquine starting dose of 200 mg by mouth every day for a 21 day cycle. Sirolimus starting dose of 2 mg by mouth every day for a 21 day cycle.
干预措施: Hydroxychloroquine (Drug)
Hydroxychloroquine + Sirolimus
Hydroxychloroquine starting dose of 200 mg by mouth every day for a 21 day cycle. Sirolimus starting dose of 2 mg by mouth every day for a 21 day cycle.
干预措施: Sirolimus (Drug)
Hydroxychloroquine + Vorinostat
Hydroxychloroquine starting dose of 200 mg by mouth every day for a 21 day cycle. Vorinostat starting dose of 200 mg by mouth per day for a 21 day cycle.
干预措施: Hydroxychloroquine (Drug)
Hydroxychloroquine + Vorinostat
Hydroxychloroquine starting dose of 200 mg by mouth every day for a 21 day cycle. Vorinostat starting dose of 200 mg by mouth per day for a 21 day cycle.
干预措施: Vorinostat (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Sirolimus or Vorinostat in Combination with Hydroxychloroquine in Participants with Advanced Cancers
时间窗: 21 day cycles, approximately 4 weeks for DLT assessment
Maximum tolerated dose (MTD) defined defined as the dose level below the dose at which 2 of 6 patients experience drug-related dose limiting toxicity (DLT) in the first treatment cycle. Dose limiting toxicity (DLT) defined as: Any grade 3 or 4 non-hematologic toxicity as defined in the NCI CTC v3.0 that is possibly, probably or definitely related to any of the three study medications, even if expected. This is to include symptoms/signs of vascular leak or cytokine release syndrome; or any severe or life-threatening complication or abnormality not defined in the NCI-CTCAE that is possibly, probably or definitely related to the therapy.
次要结局
- Antitumor Efficacy of Sirolimus or Vorinostat in Combination with Hydroxychloroquine in Participants with Advanced Cancers(6 weeks)