A Phase I Dose-Escalation Study of the BRAF Inhibitor Vemurafenib (Zelboraf®) in Combination With an mTOR Inhibitor, Everolimus (Afinitor®) or Temsirolimus (Torisel®), in Subjects With Advanced Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 27
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of Combination Vemurafenib
研究概览
简要总结
The goal of this clinical research study is to find the highest tolerable dose of vemurafenib that can be given in combination with either everolimus or temsirolimus. The safety of these drug combinations will also be studied.
Vemurafenib is designed to block BRAF inside the cancer cells, which is a mutation that is involved in cancer cell growth.
Temsirolimus and everolimus are designed to block the growth of cancer cells, which may cause cancer cells to die.
详细描述
Study Drug Administration:
If you are found to be eligible to take part in this study, your doctor will decide whether you will receive either everolimus or temsirolimus
You will be assigned to a dose level of vemurafenib based on when you join this study. Up to 5 dose levels of vemurafenib will be tested. Up to 6 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. 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 vemurafenib is found.
Study Drug Administration:
You will take 3 vemurafenib tablets in the morning and 3 tablets in the evening.You will take it every day during each 28-day study cycle. You will take vemurafenib in combination with either 1 tablet of everolimus every day of each cycle or you will receive temsirolimus by vein over 30-60 minutes on Days 1, 8, 15, and 22 of each cycle.
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
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmation of BRAF mutation-positive malignancy is required for selection of patients for vemurafenib therapy
- •Measurable or non-measurable disease by RECIST 1.
- •Patients with advanced cancer should be refractory to standard therapy, relapsed after standard therapy, or have no standard therapy available that improves survival by at least three months.
- •Patients must be at least 3 weeks past receiving cytotoxic therapy and at least 5 half-lives after their previous treatment or 3 weeks, whichever is shorter, after biologic therapy. Patients may receive palliative radiotherapy immediately or during treatment provided that not all target lesions are radiated.
- •ECOG performance status </= 2 (Karnofsky >/= 60%; Lansky Score >/= 50).
- •Patients must have normal organ and marrow function defined as: absolute neutrophil count >/=1,000/mL; platelets >/=50,000/mL; creatinine < 2.0; total bilirubin < 2.0; ALT(SGPT) </= 3 X ULN; Exception for patients with liver metastasis: ALT(SGPT) </= 5 X ULN.
- •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.
- •Ability to understand and the willingness to sign a written informed consent document.
排除标准
- •Patients with uncontrolled concurrent illness, including but not limited to: ongoing or active infection requiring hospitalization; psychiatric illness/social situations that would limit compliance with study requirements.
- •Exclusion of patients with creatinine >2.0 and bilirubin > 2.
- •Pregnant or lactating women.
- •Patients with a history of bone marrow transplant within the previous two years.
- •Patients with a known hypersensitivity to any of the components of the drug products.
- •Patients with major surgery within 30 days prior to entering the study.
- •Patients with a baseline QTc > 500 ms.
- •Patients who are unable to swallow pills.
研究组 & 干预措施
Vemurafenib + Oral Everolimus
Vemurafenib starting dose 720 mg orally twice day (morning/evening) for 28-day cycle plus Oral Everolimus starting dose 5 mg daily.
干预措施: Vemurafenib (Drug)
Vemurafenib + Oral Everolimus
Vemurafenib starting dose 720 mg orally twice day (morning/evening) for 28-day cycle plus Oral Everolimus starting dose 5 mg daily.
干预措施: Everolimus (Drug)
Vemurafenib + Intravenous Temsirolimus
Vemurafenib starting dose 720 mg orally twice day (morning/evening) for 28-day cycle plus Intravenous Temsirolimus starting dose 15 mg daily on Days 1, 8, 15, and 22 of each cycle.
干预措施: Vemurafenib (Drug)
Vemurafenib + Intravenous Temsirolimus
Vemurafenib starting dose 720 mg orally twice day (morning/evening) for 28-day cycle plus Intravenous Temsirolimus starting dose 15 mg daily on Days 1, 8, 15, and 22 of each cycle.
干预措施: Temsirolimus (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Combination Vemurafenib
时间窗: First cycle of 28 day cycle
The MTD of combination Vemurafenib and Everolimus or Vemurafenib and Temsirolimus is defined as the highest dose studied in which the incidence of dose limiting toxicity (DLT) was less than one third (33%) of the participants at that dose level. DLT defined as any Grade 3 or 4 non-hematologic toxicity, as defined in NCI CTC v4.0, even if expected and believed related to study medications, any Grade 4 hematologic toxicity lasting two weeks or longer despite supportive care; Grade 3 nausea/vomiting \> 48 hours or any Grade 4 nausea/vomiting; and any other Grade 3 non-hematologic toxicity, including symptoms/signs of vascular leak or cytokine release syndrome; or any severe or life-threatening complication or abnormality not defined in NCI-CTCAE that is attributable to therapy.
次要结局
- Tumor Response(4 months)