Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: A phase I study

Department of Neurological Surgery, University of California San Francisco, 400 Parnassus Avenue, A808, San Francisco, CA 94143-0350, USA.
Neuro-Oncology (Impact Factor: 5.56). 02/2010; 12(6):608-13. DOI: 10.1093/neuonc/nop070
Source: PubMed


We conducted a phase I study to determine the safety and recommended phase II dose of enzastaurin (oral inhibitor of the protein kinase C-beta [PKCbeta] and the PI3K/AKT pathways) when given in combination with radiation therapy (RT) plus temozolomide to patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Patients with Karnofsky performance status > or =60 and no enzyme-inducing anti-epileptic drugs received RT (60 Gy) over 6 weeks, concurrently with temozolomide (75 mg/m(2) daily) followed by adjuvant temozolomide (200 mg/m(2)) for 5 days/28-d cycle. Enzastaurin was given once daily during RT and adjuvantly with temozolomide; the starting dose of 250 mg/d was escalated to 500 mg/d if < or =1/6 patients had dose-limiting toxicity (DLT) during RT and the first adjuvant cycle. Patients continued treatment for 12 adjuvant cycles unless disease progression or unacceptable toxicity occurred. Twelve patients enrolled. There was no DLT in the first 6 patients treated with 250 mg enzastaurin. At 500 mg, 2 of 6 patients experienced a DLT (1 Grade 4 and 1 Grade 3 thrombocytopenia). The patient with Grade 3 DLT recovered to Grade <1 within 28 days and adjuvant temozolomide and enzastaurin was reinitiated with dose reductions. The other patient recovered to Grade <1 toxicity after 28 days and did not restart treatment. Enzastaurin 250 mg/d given concomitantly with RT and temozolomide and adjuvantly with temozolomide was well tolerated and is the recommended phase II dose. The proceeding phase II trial has finished accrual and results will be reported in 2009.

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Available from: Susan M Chang, Oct 05, 2015
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    • "Enzastaurin was also well tolerated in all published phase I and II studies, both alone with radiotherapy and when temozolomide was added. Haematological toxicity, nausea, fatigue and constipation were the most troublesome side-effects [39]. Eight published phase II trials were identified; one involving sorafenib [46], two sunitinib [50] [52], one vandetanib [56] and three investigating enzastaurin [40e42] and one everolimus [44]. "
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    ABSTRACT: Recent drug discovery developments in the field of small molecule targeted agents have led to much interest in combining these with radiotherapy. There are good preclinical data to suggest this approach worthy of investigation and in this review we discuss how this has translated into recent clinical trials. The outcome of clinical trials investigating radiotherapy/targeted drug combinations published in the last 5 years is discussed, as are trials in progress. The perceived future opportunities and challenges in the development of this exciting area are considered.
    Clinical Oncology 03/2014; 26(5). DOI:10.1016/j.clon.2014.02.006 · 3.40 Impact Factor
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    • "The safety and clinical activity of enzastaurin in association with standard RT and TMZ treatment in patients with newly diagnosed GBM have been explored in a few clinical trials (Table 1). Butowski et al95 reported a single-institution Phase I dose-escalation trial of enzastaurin with standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma. Enzastaurin was administered at doses of 250 mg (n = 6) or 500 mg (n = 6) daily from the night before the beginning of RT. "
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    ABSTRACT: The expansion in understanding the molecular biology that characterizes cancer cells has led to the rapid development of new agents to target important molecular pathways associated with aberrant activation or suppression of cellular signal transduction pathways involved in gliomagenesis, including epidermal growth factor receptor, vascular endothelial growth factor receptor, mammalian target of rapamycin, and integrins signaling pathways. The use of antiangiogenic agent bevacizumab, epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib, mammalian target of rapamycin inhibitors temsirolimus and everolimus, and integrin inhibitor cilengitide, in combination with radiation therapy, has been supported by encouraging preclinical data, resulting in a rapid translation into clinical trials. Currently, the majority of published clinical studies on the use of these agents in combination with radiation and cytotoxic therapies have shown only modest survival benefits at best. Tumor heterogeneity and genetic instability may, at least in part, explain the poor results observed with a single-target approach. Much remains to be learned regarding the optimal combination of targeted agents with conventional chemoradiation, including the use of multipathways-targeted therapies, the selection of patients who may benefit from combined treatments based on molecular biomarkers, and the verification of effective blockade of signaling pathways.
    OncoTargets and Therapy 08/2013; 6:1079-95. DOI:10.2147/OTT.S48224 · 2.31 Impact Factor
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    ABSTRACT: The paradigm for treating patients with glioblastoma multiforme (GBM) is shifting from a purely cytotoxic approach to one that incorporates antiangiogenic agents. These are thought to normalize the tumor vasculature and have shown improved disease management in patients with recurrent disease. How this vascular remodeling evolves during the full course of therapy for patients with newly diagnosed GBM and how it relates to radiographic response and outcome remain unclear. In this study, we examined 35 patients who were newly diagnosed with GBM using dynamic susceptibility contrast (DSC) MRI in order to identify early predictors of radiographic response to antiangiogenic therapy and to evaluate changes in perfusion parameters that may be predictive of progression. After surgical resection, patients received enzastaurin and temozolomide, both concurrent with and adjuvant to radiotherapy. Perfusion parameters, peak height (PH) and percent recovery, were calculated from the dynamic curves to assess vascular density and leakage. Six-month radiographic responders showed a significant improvement in percent recovery between baseline and 2 months into therapy, whereas 6-month radiographic nonresponders showed significantly increased PH between baseline and 1 month. At 2 months into therapy, percent recovery was predictive of progression-free survival. Four months prior to progression, there was a significant increase in the standard deviation of percent recovery within the tumor region. DSC perfusion imaging provides valuable information about vascular remodeling during antiangiogenic therapy, which may aid clinicians in identifying patients who will respond at the pretherapy scan and as an early indicator of response to antiangiogenic therapy.
    Neuro-Oncology 10/2010; 13(1):119-31. DOI:10.1093/neuonc/noq143 · 5.56 Impact Factor
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