A Phase II Trial of Avastin and Temsirolimus Following Tyrosine Kinase Inhibitor Failure in Patients With Advanced Renal Cell Carcinoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 41
- 试验地点
- 3
- 主要终点
- 4-month Progression-Free Survival Rate
研究概览
简要总结
This is a single-arm phase II trial evaluating the combination of avastin and temsirolimus in patients with metastatic renal cell cancer (RCC) including both histologically confirmed clear cell (cc) or non-clear cell (ncc) subtypes. Patients must have experienced disease progression or intolerable toxicity with a vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitor (TKI) (e.g. sorafenib, sunitinib, pazopanib). Only 2 prior VEGF therapies are allowed. The purpose of this research study is to evaluate efficacy of the combination against an historical control. Temsirolimus has been approved by the Food and Drug Administration (FDA) in the treatment of renal cell carcinoma. Avastin has been approved by the FDA for other types of cancers but not renal cell carcinoma.
详细描述
Avastin, a humanized IgG1 monoclonal antibody (MAb), inhibits vascular endothelial growth factor (VEGF). VEGF is one of the most potent and specific proangiogenic factors and has been identified as a crucial regulator of both normal and pathological angiogenesis. Temsirolimus specifically inhibits the mammalian target of rapamycin (mTOR), a highly conserved serine/threonine kinase which regulates cell growth and metabolism in response to environmental factors. The combination avastin and temsirolimus has already demonstrated efficacy in the phase I setting
STATISTICAL CONSIDERATIONS:
The primary endpoint is 4-month PFS. The null and alternative hypotheses are 50% vs. 70%. Assuming 2 ineligible patients, the target sample size is 41 patients (39 eligible patients). The probability of concluding that the treatment is effective was >0.90 if the true rate is at least 70%. The probability of concluding that the treatment is effective was ≤ 0.10 if the true rate was 50% or less. If 24 or more patients are alive and progression-free at 4 months, then this regimen would be considered for further study.
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
- 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
- •Histologically confirmed renal cell carcinoma in either primary or metastatic lesions. Non-clear histology will be allowed.
- •Disease progression on a VEGF-targeted tyrosine kinase inhibitor as the most recent therapy or have experienced intolerable toxicity so as require discontinuation. Only one prior VEGF-targeted tyrosine kinase inhibitor.
- •Must be off of VEGF-targeted tyrosine kinase inhibitor for 2 weeks or greater.
- •One measurable lesion which is not curable by standard radiation therapy or surgery.
- •The enrolling site must agree to obtain paraffin-embedded tumor blocks or at least 10 unstained, paraffin-embedded slides for submission for correlative studies.
- •18 years of age or older
- •ECOG Performance Status of 0 or 1
- •Baseline laboratory values as outlined in the protocol
- •Life expectancy of greater than 3 months
- •No prior malignancy diagnosed within the past three years, other than superficial basal cell and superficial squamous cell, or carcinoma in situ of the cervix.
排除标准
- •Known CNS disease, except for treated brain metastases
- •Previously treated with avastin or mTOR inhibitors
- •Other then VEFG-targeted TKI, patients may only have had prior immunotherapy or chemotherapy for stage IV disease
- •History of allergic reaction to Chinese hamster ovary cell products, other recombinant antibodies, or compounds of similar chemical or biologic composition to avastin or temsirolimus
- •History of bleeding diathesis or coagulopathy. Therapeutic anticoagulants are allowed
- •Patients with clinically significant cardiovascular disease
- •Patients receiving enzyme-inducing antiepileptic drugs or any other CYP3A4 inducer such as rifampin or St. John's wort
- •No serious non-healing wound, ulcer or bone fracture
- •No uncontrolled intercurrent illness including , but not limited to, ongoing active infection requiring parental antibiotics or psychiatric illness/social situations that would limit compliance with study requirements
- •HIV-positive receiving combination anti-retroviral therapy
- •Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study
- •Core biopsy or other minor surgical procedure, excluding placement of vascular access device, within 7 days prior to enrollment on study
- •History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
- •Known hypersensitivity to any component of avastin or temsirolimus
- •Life expectancy of less than 12 weeks
- •History of hemoptysis within 1 month prior to day 1
研究组 & 干预措施
bevacizumab and temsirolimus
bevacizumab: given intravenously at a dose of 10mg/kg every 2 weeks (days 1 and 15)
temsirolimus: given intravenously at a dose of 25mg weekly on days 1, 8, 15, and 22
1 cycle=28-days
There were no dose reductions for bevacizumab allowed. If bevacizumab was held, the same dose would be used if treatment were resumed. If temsirolimus was held, the same or a reduced dose (15mg IV weekly) could be used upon resumption of therapy. Treatment was continued until the development of unacceptable toxicity or progression.
干预措施: bevacizumab (Drug)
bevacizumab and temsirolimus
bevacizumab: given intravenously at a dose of 10mg/kg every 2 weeks (days 1 and 15)
temsirolimus: given intravenously at a dose of 25mg weekly on days 1, 8, 15, and 22
1 cycle=28-days
There were no dose reductions for bevacizumab allowed. If bevacizumab was held, the same dose would be used if treatment were resumed. If temsirolimus was held, the same or a reduced dose (15mg IV weekly) could be used upon resumption of therapy. Treatment was continued until the development of unacceptable toxicity or progression.
干预措施: temsirolimus (Drug)
结局指标
主要结局
4-month Progression-Free Survival Rate
时间窗: Disease evaluations occurred every 8 weeks (+/- 1 wk) on treatment. Relevant for this endpoint was disease status at 4 months.
4-month progression-free survival rate was defined as the percentage of participants absent death or progression based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST) before 4 months. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
次要结局
- Objective Response Rate(Disease evaluations occurred every 8 weeks (+/- 1 wk) on treatment; Treatment continued until disease progression or unacceptable toxicity. Median (range) of treatment duration for this study cohort was 5 cycles (1-39) [1 cycle=28days].)
- Overall Survival(Median follow-up for survival in this study cohort is 56 months.)
研究者
David F. McDermott, MD
Principal Investigator
Dana-Farber Cancer Institute