Phase II Study of Everolimus (RAD001, Afinitor®) for Children With Recurrent or Progressive Ependymoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 11
- 试验地点
- 4
- 主要终点
- Objective Response Rate (Complete Response Rate and Partial Response Rate) Following Treatment With Everolimus for Children With Recurrent or Progressive Ependymomas.
研究概览
简要总结
The purpose of this study is to evaluate the anti-tumor activity of Everolimus among children with recurrent or progressive ependymoma. Recurrent or progressive ependymoma is incurable and has very limited treatment options. The rationale for this study is based upon both pre-clinical and clinical considerations: Immunohistochemistry studies have demonstrated that 20 out of 23 (87%) pediatric ependymomas are immunoreactive for phosphorylated S6, a biomarker that often predicts response to mTOR pathway-targeted therapy. Furthermore, children with with multiply recurrent ependymomas have had objective and durable responses to the mTOR inhibitor, Sirolimus (Rapamune, Pfizer). As a result of this pre-clinical and clinical data, this study will further investigate the activity of an mTOR pathway inhibitor, Everolimus, against children with recurrent or progressive ependymomas. In this study, Everolimus will be administered at a dose and schedule that have previously been demonstrated as safe and effective in children. Children may take Everolimus for up to 2 years on this study, until tumor progression or unacceptable toxicity.
详细描述
Ependymoma is the third most common central nervous system neoplasm in children, accounting for approximately 10% of childhood brain tumors. Although the prognosis for children with newly-diagnosed completely resected ependymomas is often good, children with incompletely resected tumors often suffer repeated episodes of tumor progression and die as a result of their tumor. The prognosis for children with recurrent or progressive ependymomas is especially dismal and the majority of children with recurrent or progressive ependymomas will eventually succumb to their tumor within 8.7 to 24 months. At the time of tumor recurrence, therapeutic options are limited. A recent report by Merchant and co-workers described several long-term survivors after tumor recurrence when treated with a second course of radiation therapy.
Unfortunately, although chemotherapy occasionally demonstrates anti-tumor activity against recurrent ependymoma, but responses are rarely durable.12 Indeed, a recent review by Bouffet and co-workers concluded that the frequency of durable responses of recurrent ependymomas to chemotherapy was disappointing and encouraged a re-evaluation of the current chemotherapeutic approach to intracranial ependymoma and that studies are needed to identify new biological targets to inform future clinical trials.
Everolimus is a novel derivative of rapamycin. It has been in clinical development since 1996 as an immunosuppressant in solid organ transplantation. Everolimus is approved in Europe and other global markets (trade name: Certican®) for cardiac and renal transplantation, and in the United States (trade name: Zortress®) for the prevention of organ rejection of kidney transplantation. Everolimus was developed in oncology as Afinitor® and was approved for advanced renal cell carcinoma (RCC) in 2009. In 2010, Afinitor® received United States (US) approval for patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS). Everolimus is also available as Votubia® in the European Union (EU) for patients with SEGA associated with TS. Afinitor® was approved for "progressive pancreatic neuroendocrine tumor (PNET) in patients with unresectable, locally advanced, or metastatic disease" in 2011 in various countries, including the US and Europe. In 2012, Afinitor® received approval for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2- negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. Furthermore in 2012, Afinitor® received approval for the treatment of adult patients with TSC who have renal angiomyolipoma not requiring immediate surgery.
At the cellular and molecular level, Everolimus acts as a signal transduction inhibitor. It selectively inhibits mTOR (mammalian target of rapamycin), a key protein kinase which regulates cell growth, proliferation and survival. The mTOR kinase is mainly activated via the phosphatidylinositol 3-kinase (PI3-Kinase) pathway through AKT/PKB and the tuberous sclerosis complex (TSC1/2). Mutations in these components or in PTEN, a negative regulator of PI3-kinase, may result in their dysregulation. Abnormal functioning of various components of the signaling pathways contributes to the pathophysiology of numerous human cancers. Various preclinical models have confirmed the role of this pathway in tumor development.
The main known functions of mTOR include the following:
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
- 2 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis and Age: Ependymoma (WHO grade II) or Anaplastic Ependymoma (WHO grade III) that has relapsed or become refractory to standard therapy. Patients must have had histologic verification of their malignancy at original diagnosis or time of recurrence. Age must be ≥ 2 years and ≤ 21 years of age at study entry.
- •Tumor tissue must be available (from either time of initial diagnosis or relapse) and submitted for central pathology review and correlative biological studies.
- •Performance status: Lansky ≥ 50% for patients ≤ 10 years of age or Karnofsky ≥ 50% for patients > 10 years of age.
- •Adequate bone marrow, liver and renal function.
- •Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x the upper limit of normal.
- •Patients must have measurable residual disease, defined as tumor that is measurable in two diameters on MRI. Diffuse leptomeningeal disease is not considered measurable.
- •Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy prior to participating in this trial. No prior myelosuppressive chemotherapy for 28 days prior to study enrollment. Must not have received craniospinal radiation therapy within 24 weeks prior to study entry and no involved field radiation therapy for 12 weeks prior to study enrollment. If patients received prior monoclonal antibody treatment, at least three half-lives must be elapsed by the time of treatment initiation. No investigational drugs for 4 weeks prior to study enrollment.
- •MRI of the brain and the complete spine: All patients must have an MRI of the brain and spine that has measurable tumor (not only diffuse leptomeningeal tumor) within two weeks prior to study enrollment.
排除标准
- •Prior treatment with Everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus).
- •Concommitant use of medications known to have inhibition or induction of CYP3A enzymes. Systemic corticosteroids (e.g., dexamethasone is a CYP3A inducer) are not allowed. Inhaled corticosteroids are allowed.
- •Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral Everolimus.
- •Uncontrolled diabetes mellitus as defined by HbA1c > 8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary.
研究组 & 干预措施
Everolimus
The recommended dose of Everolimus is 4.5 mg/m2/dose, once daily for up to 2 years, until disease progression or unacceptable toxicity occurs.
干预措施: Everolimus (Drug)
结局指标
主要结局
Objective Response Rate (Complete Response Rate and Partial Response Rate) Following Treatment With Everolimus for Children With Recurrent or Progressive Ependymomas.
时间窗: 2 years
Complete Response: Disappearance of all enhancing measurable and non-measurable disease Partial Response: ≥50% decrease in sum of products of perpendicular diameters of all measurable enhancing lesions compared with baseline
次要结局
- Duration of Response(2 years)
- Number of Participants With Upregulated Biomarkers of mTOR Activation(2 years)
- Progression Free Survival (PRS)(2 years)
- Event Free Survival (EFS)(2 years)
- Number of Participants With Adverse Events as a Measure of Safety and Tolerability.(2 years)
研究者
Daniel Bowers
Professor of Pediatrics
University of Texas Southwestern Medical Center