Phase II Study: Systemic Treatment With iv ZK219477-Epothilone in Recurrent Glioblastoma Patients
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Progression Free Survival at six months (PFS-6).
研究概览
简要总结
The purpose of this single arm phase II study is to evaluate safety and efficacy of ZK 219477 in the treatment of temozolomide pre-treated, recurrent GBM patients.
详细描述
Malignant gliomas remain among the most devastating cancers, and especially for recurrent GBM no standard treatment has been established to date.
ZK 219477 is a fully synthetic analogue of Epothilone B, a naturally occurring cytotoxic substance. ZK 219477 inhibits microtubule depolymerization, causing cell cycle blockage in G2/M phase and induction to apoptosis. This mechanism of action is similar to that of taxanes (paclitaxel and docetaxel), but epothilones retain activity against multi-drug resistance (MDR) tumours. ZK 219477 demonstrated both in vitro and in vivo considerable anti-tumour activity against a wide range of malignancies, and it is now about to enter phase II studies in a number of selected indications. In pre-clinical model ZK 219477 has demonstrated anti-tumorigenic activity for gliomas tumours both in vitro and in vivo.
ZK 219477 has the ability to cross the blood-brain barrier, a fundamental characteristic for a potential GBM chemotherapy. In a preclinical PK study, similar concentrations of ZK 219477 were detected in plasma (1.2 μg/ml) and brain (0.9 μg/g) after 10 min after i.v. application in scid mice. The AUC brain/AUC plasma was about 0.8, indicating a free access to the brain (Hoffmann J et al. 2004, European Journal Cancer Supplement 2, N 8, p. 159, Abstract 521, ref.17). ZK 219477 produced strong antiproliferative activity in the human glioma cell line U373 inoculated subcutaneous in nude mice (2 mg/kg and 9 mg/kg) as well as paclitaxel (8 mg/kg), but on the contrary of paclitaxel, only ZK 219477 demonstrated antitumour activity against U373 implanted in nude mice (9 mg/kg): 8 complete response out 9 treated mice.
Of interest for GBM indication, ZK 219477 is not metabolized by liver cytochrome P450, which is induced by phenytoin and other anti-convulsion drug, commonly used in post-surgery GBM patients.
The purpose of this single arm phase II study is to evaluate safety and efficacy of ZK 219477 in the treatment of pre-treated, recurrent GBM patients. Aim of the study: The purpose of this single arm phase II study is to evaluate safety and efficacy of ZK 219477 in the treatment of pre-treated, recurrent GBM patients. An optional PK study will be performed in selected patients.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age between 18 and 70 years
- •Life expectancy of at least 3 months
- •Presence of at least one bi-dimensionally measurable lesion on gadolinium (Gd)-enhanced MRI, indicating progressive or recurrent disease at least 8 weeks after standard external-beam radiotherapy
- •Recurrence or progression after treatment with radiotherapy and temozolomide. Also patients with residual disease after surgery for recurrent GBM will be included
- •Adequate bone marrow reserve (leukocytes ≥ 3,500/ml, ANC ≥ 1,500/ml, platelets ≥100,000/ ml); normal baseline liver (serum bilirubin ≤ 20 /mol/ L), renal (serum creatinine <150 /mol/L) and cardiac function
- •Absence of infectious disease, debilitating chronic diseases, and known psychiatric disorders
- •Corticosteroid dose stable for at least 1 week
- •Adequate recovery from previous surgery, radiation and chemotherapy
- •Negative pregnancy test at enrolment in females of child-bearing potential
- •Agreement to use highly effective contraception methods in adults of reproductive potential
- •Fully informed written consent
排除标准
- •Pregnant women
- •Patients who have had chemotherapy or radiotherapy within 4 weeks
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZK219477
- •Uncontrolled inter current illness including, but not limited, to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •HIV-infection
- •Any prior treatment with epothilones, other tubulin-targetting as taxanes (e.g. paclitaxel, docetaxel) and vinca alkaloids (e.g. vincristine, vinblastine, vinorelbine)
- •Peripheral neuropathy
- •Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix
- •Active infection
- •Breast-feeding
- •Subjects who have received an experimental drug or have participated in a clinical trial within 3 months prior to screening
- •Employees of the investigator or study centre with direct involvement in the proposed study or other studies under the direction of that investigator or study centre
研究组 & 干预措施
ZK-EPO
administered iv for 3 h every 21 days; dose reductions to 12 or 9 mg/m2 ZK-EPO were allowed in order to manage any treatment-related toxicity.
干预措施: ZK 219477 (Drug)
结局指标
主要结局
Progression Free Survival at six months (PFS-6).
时间窗: 6 months
次要结局
- Response rates (CR +PR)(2 years)
- Safety evaluation according to CTC-AE(2 years)
- Median Survival Time (MST)(2 years)
研究者
Antonio Silvani
MD
Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta