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ET-03. THE EFFICACY OF TEMOZOLOMIDE IN VITRO AND IN PATIENTS WITH NEWLY DIAGNOSED GBM IS ENHANCED BY ADJUVANT EXPOSURE TO ALTERNATING ELECTRIC FIELDS (TTFIELDS)


Posted on: 08/29/2008

From:

Abstracts for the Thirteenth Annual Meeting of the Society for Neuro-Oncology

November 20–23, 2008

ET-03. THE EFFICACY OF TEMOZOLOMIDE IN VITRO AND IN PATIENTS WITH NEWLY DIAGNOSED GBM IS ENHANCED BY ADJUVANT EXPOSURE TO ALTERNATING ELECTRIC FIELDS (TTFIELDS)
Eilon Kirson1, Vladimir Dbaly2, Frantisek Tovarys2, Josef Vymazal3, Rosa Schneiderman4, Yoram Wasserman5, and Yoram Palti1; 1NovoCure Ltd., Haifa, Israel; 2Neurosurgery, Na Homolce Hospital, Prague, Czech Republic; 3Radiology, Na Homolce Hospital, Prague, Czech Republic; 4Biology, NovoCure Ltd., Haifa, Israel; 5Engineering, NovoCure Ltd., Haifa, Israel.

BACKGROUND: Alternating electric fields (TTFields) have been shown to exert anti-tumor activity, destroying cycling cells during mitosis. Preliminary clinical experience suggests efficacy against recurrent glioma; this technique is currently undergoing phase III evaluation in patients with recurrent glioblastoma. In vitro synergy with various chemotherapeutic agents has been shown in breast and lung cancer cell lines (Kirson et al, AACR 2007).

METHODS: In the present study, the effects of TTFields alone and in combination with DTIC were tested in human glioma (GBM) cells in vitro (U-87). Subsequently, the effects of TTFields in combination with maintenance temozolomide (TMZ) were tested in an open-label, single-arm, prospective, pilot clinical trial. Ten patients (median age 54 years, KPS > 70, gross total tumor resection in 4 patients [40%]) with newly diagnosed GBM were treated with standard TMZ/RT. During the maintenance TMZ administration, TTFields were applied continually (18 hours a day, on average) for up to 18 months . All patients were followed on a monthly basis (including monthly contrast magnetic resonance imaging
of the brain). The primary endpoints were feasibility and toxicity, time to disease progression, and overall survival. Results were compared to concurrent and historical controls.

RESULTS: In vitro, full additivity of the inhibitory effects of DTIC and TTFields was observed when both treatments were applied concomitantly to GBM cells in culture. This finding was true for all DTIC concentrations tested. In the pilot clinical trial, no device–related, systemic, adverse events were noted throughout the treatment with TTFields (cumulative treatment time more than 170 months; median administration time 12 months). Over time, a mild to moderate skin irritation appeared beneath the electrode gel in all patients. Median time to disease progression was 155 weeks in patients treated with combined TMZ and TTFields, compared to 31 weeks in concurrent control patients treated with TMZ alone (hazard ratio 3.7; 95% confidence interval 2.1–6.7). Half the patients were still progression-free at the end of the trial. Median overall survival was . 40 months in patients treated with combined TMZ and TTFields, compared to 14.7 months reported for historical controls (Stupp et al, 2004). Eight of the 10 patients were still alive at the end of this study.

CONCLUSIONS: These promising findings suggest that TTFields can be applied over many months without significant toxicity. The combination with standard TMZ chemotherapy may greatly enhance the anti-tumor effect of TMZ translating into prolonged time to progression and survival.

 


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