Epothilone in Recurrent Glioblastoma Patients
Recruitment status was Recruiting
|First Received Date ICMJE||November 7, 2006|
|Last Updated Date||November 7, 2006|
|Start Date ICMJE||June 2006|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
||Progression Free Survival at six months (PFS-6).|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||No Changes Posted|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Epothilone in Recurrent Glioblastoma Patients|
|Official Title ICMJE||Phase II Study: Systemic Treatment With iv ZK219477-Epothilone in Recurrent Glioblastoma Patients|
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.
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.
Study Design: Open, monocentric, not randomised, single arm, phase II study. Study medication: ZK 219477 epothilone B analog. Study Population: 15 recurrent glioblastoma patients previously treated by surgery, conventional radiotherapy and chemotherapy with temozolomide (TMZ. The 15 patients for this study, represent the first stage of recruitment according to the statistical design.
Treatment will be administered on an inpatient basis. ZK 219477 will be administered as an i.v. infusion of 3 hours duration at a dose of 16 mg/m2 BSA every three weeks.
Two dose reductions are allowed in order to manage toxicities: 12 mg/m2 and 9 mg/m2.
Efficacy evaluation. Primary end-point: Progression Free Survival at 6 months (PFS-6). Secondary end-points: Response rates (CR +PR), Median Survival Time (MST). Safety evaluation. Treatment toxicity will be assessed using CTCAE, Version 3.0, except for neurological toxicity that will be assessed also by means of the Scottish Gynaecological Cancer Trials Group (SGCTG) Neurotoxicity Score and electromyography.
A group-sequential design will be used with the chance of remaining alive and free of progression at 6 months, called “response”, as primary endpoint. The null hypothesis of a response rate ≤ 10% will be tested based on the binomial distribution of the response endpoint at a nominal significance level of 0.10 (one-sided). If the observed response rate in the 15 patients is < 20%, the null hypothesis will be accepted and study failure will be concluded. If the observed response rate is ≥ 20% (i.e., at least three out of the 15 patients show a response after 6 months), then consideration would be given to studying further. If the observed response rate amounts to at least 5 out of the initial 15 patients, the null hypothesis will be rejected and the study may be stopped after the first stage. Secondary end-points: PFS and MST will be estimated using the Kaplan–Meier method.
Response, age, KPS, number of surgical procedures performed, previous low grade, and time between end of radiotherapy and start of chemotherapy will be considered variables possibly related to TTP and the time interval between start of chemotherapy and death from any cause (MST). Descriptive statistics with these classified time-to-event variables as subgroups will be provided
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Non-Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Intervention ICMJE||Drug: ZK 219477|
|Study Arm (s)||Not Provided|
|Publications *||Klar U, Buchmann B, Schwede W, Skuballa W, Hoffmann J, Lichtner RB. Total Synthesis & Antitumor Activity of ZK-EPO: The First Fully Synthetic Epothilone in Clinical Development. Angew Chem Int Ed Engl. 2006 Sep 27; [Epub ahead of print] No abstract available.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Completion Date||September 2007|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
|Ages||18 Years to 70 Years|
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||Italy|
|NCT Number ICMJE||NCT00397072|
|Other Study ID Numbers ICMJE||ZK219477IV|
|Has Data Monitoring Committee||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||Istittuto Nazionale Neurologico Carlo Besta|
|Collaborators ICMJE||Not Provided|
|Information Provided By||Istittuto Nazionale Neurologico Carlo Besta|
|Verification Date||November 2006|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP