A Phase Ib/II Study of AZD2171 in Combination With Daily Temozolomide and Radiation in Patients With Newly Diagnosed Glioblastoma Not Taking Enzyme-Inducing Anti-epileptic Drugs
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 2
- 主要终点
- Progression-free survival (Phase II)
研究概览
简要总结
This phase I/II trial is studying the side effects and best dose of cediranib to see how well it works when given together with temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma. Cediranib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving cediranib together with temozolomide and radiation therapy may kill more tumor cells.
详细描述
PRIMARY OBJECTIVES:
I. To determine the safety profile and optimal dose of AZD2171 (cediranib) (15mg or 20mg or 30mg) in combination with temozolomide and radiation in patients with newly diagnosed glioblastoma (Phase Ib) II. To determine median progression-free survival of patients with newly diagnosed glioblastoma treated with AZD2171 in combination with temozolomide and radiation (Phase II)
SECONDARY OBJECTIVES:
I. To determine the radiographic response proportion in newly diagnosed glioblastoma patients with measurable disease. (Phase II) II. To determine the median overall survival. (Phase II) III. To determine the "vascular normalization" window in newly diagnosed glioblastoma patients by the application of serial, non-invasive, MRI parameters. (Phase II) IV. To measure the glucose metabolism changes in a subset of newly diagnosed glioblastoma patients by performing FDG PET studies. (Phase II) V. Measurement of circulating endothelial and progenitor cells and plasma levels of VEGF-A; VEGF-B; VEGF-C; VEGF-D; sVEGFR1, sVEGFR2, bFGF, PlGF, PDGF-AA; PDGF-AB; PDGF-BB; SDF1α; tumstatin; thrombospondin-1; interleukin-8; collagen IV sICAM1, sVCAM1 as markers for response to AZD2171 in newly diagnosed glioblastoma patients. (Phase II) VI. Correlation of treatment outcomes with pre-AZD2171 tumor specimens with respect to cell proliferation, apoptosis, microvascular density (MVD), basement membrane and pericyte coverage, angiopoietin-1 and -2 expression to determine whether these immunohistochemical analyses can be predictive of the response to AZD2171. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of cediranib followed by a phase II 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 glioblastoma
- •Newly diagnosed disease
- •Scheduled to receive standard post-surgical (i.e., biopsy or resection) temozolomide and radiotherapy
- •Must have residual, contrast-enhancing tumor (≥ 1 centimeter in ≥ 1 dimension)
- •Patients must be maintained on a stable corticosteroid regimen for 5 days prior to their baseline scan and for 5 days prior to their first vascular MRI; the dose of steroids should remain the same during the baseline vascular MRIs
- •Archival tumor tissue available for molecular analysis
- •No intratumoral hemorrhage or peritumoral hemorrhage by MRI
- •Karnofsky performance status 60-100%
- •Leukocytes ≥ 3,000/mcl
- •Absolute neutrophil count ≥ 1,500/mcL
- •Platelet count ≥ 100,000/mcL
- •Hemoglobin ≥ 8 g/dL
- •Total bilirubin normal
- •AST/ALT ≤ 2.5 times upper limit of normal
- •Creatinine normal OR creatinine clearance ≥ 60 mL/min
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception
- •Proteinuria ≤ 1+ on two consecutive dipsticks ≥ 7 days apart
- •Mini-mental status examination score ≥ 15
- •Must be able to tolerate MRI and must consent to participate in additional Vascular Imaging Procedures per protocol
- •CT scans cannot be substituted for MRI
- •Mean QTc ≤ 500 msec (with Bazett's correction) by electrocardiogram
- •No concurrent malignancy except curatively treated basal cell or squamous cell carcinoma skin cancer or carcinoma in situ of the cervix or breast
- •Patients with prior malignancies must be disease-free for ≥ 5 years
- •No history of familial long QT syndrome or other significant ECG abnormality
- •No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib
- •No uncontrolled intercurrent illness including, but not limited to, any of the following:
- •Hypertension (e.g., blood pressure > 140/90 mm Hg)
- •Ongoing or active infection
- •Symptomatic congestive heart failure
- •Unstable angina pectoris
- •Cardiac arrhythmia
- •Psychiatric illness/social situations that would preclude study compliance
- •No known coagulopathy that increases risk of bleeding
- •No history of clinically significant hemorrhages in the past
- •No New York Heart Association class III-IV heart disease
- •No condition requiring concurrent drugs or biologics with proarrhythmic potential
- •No other concurrent chemotherapy agents, investigational agents, or biologic therapy
- •No prior chemotherapy, radiotherapy, or any experimental therapy for this disease
- •No prior IV bevacizumab for any other medical condition
- •No prior carmustine implant (Gliadel Wafer)
- •No prior brachytherapy or radiosurgery for this disease
- •More than 30 days since prior and no other concurrent investigational agents or participation in an investigational therapeutic trial
- •At least 2 weeks since prior and no concurrent enzyme-inducing anti-epileptic drugs (EIAEDs)
- •Concurrent non-EIAEDs allowed
- •No concurrent CYP450-inducing anticonvulsants
- •No concurrent anticoagulants (e.g., dalteparin, warfarin, or low-molecular weight heparin)
- •If patients require warfarin or other anticoagulants (e.g., low-molecular weight heparin) while on study, then patient may continue treatment
- •No concurrent combination antiretroviral therapy for HIV-positive patients
- 另有 3 项未显示
排除标准
- 未提供
研究组 & 干预措施
Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)
See Detailed Description
干预措施: Cediranib Maleate (Drug)
Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)
See Detailed Description
干预措施: Diffusion Tensor Imaging (Procedure)
Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)
See Detailed Description
干预措施: Diffusion Weighted Imaging (Procedure)
Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)
See Detailed Description
干预措施: Dynamic Contrast-Enhanced Magnetic Resonance Imaging (Procedure)
Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)
See Detailed Description
干预措施: Fludeoxyglucose F-18 (Radiation)
Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)
See Detailed Description
干预措施: Intensity-Modulated Radiation Therapy (Radiation)
Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)
See Detailed Description
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)
See Detailed Description
干预措施: Perfusion Magnetic Resonance Imaging (Procedure)
Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)
See Detailed Description
干预措施: Positron Emission Tomography (Procedure)
Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)
See Detailed Description
干预措施: Temozolomide (Drug)
结局指标
主要结局
Progression-free survival (Phase II)
时间窗: At day 218
The fraction of patients alive and free of disease progression after the MRI scan scheduled. This fraction will be compared, using a one sample, two-sided exact binomial test, to 50% progression-free survival (PFS). For safety assessment, the study will be powered to ensure at least 85% chance of observing a serious adverse event, if the probability of such an event on treatment were \>=5%.
Safety profile and optimal dose of cediranib during chemoradiotherapy (Phase I)
时间窗: Up to 30 days after the last dose
A dose-limiting toxicity of cediranib is defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications/temozolomide and occurs following the first dose of cediranib in the chemoradiation.
次要结局
- Blood biomarkers (Phase II)(Up to 1 year)
- MRI parameters (Phase II)(Up to 48 weeks)
- Tumor biomarkers (Phase II)(At baseline)