Phase II and pharmacogenomics study of enzastaurin plus temozolomide and radiation in patients with GBM.

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2050 Background: ENZ suppresses signaling through PKCβ and the PI3K/AKT pathways. Primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS). PGx parameters were assessed for correlation to clinical outcomes. Methods: Pts enrolled with newly diagnosed GBM or GS and Karnofsky performance status (KPS) ≥ 60. Treatment started < 5 weeks after diagnosis with RT 60 Gy given over 6 weeks and TMZ 75 mg/m2 given daily during RT and then adjuvantly at 200 mg/m2 on days 1-5 of a 28-day cycle. ENZ 250 mg/day was given daily during RT and adjuvantly. Twelve adjuvant cycles were planned. PGx biomarkers included: MIB, MGMT, MMR, PKC isoforms, MAPK, pCREB, EGFR, PTEN, GSK3β, VEGF, and pS6. PFS and OS were estimated by Kaplan-Meier method. Comparison to UCSF historical data used a Cox proportional hazard model to adjust for known prognostic factors. Correlation of biomarker data with clinical outcomes was assessed by log-rank test. Results: Sixty-six pts were included; 60 phase II pts (enrolled 9/07 to 11/08) and 6 pts given ENZ 250 mg from the prior phase I; 54 pts had progressed; 41 pts had died. Treatment produced a low incidence of toxicity. Median follow-up for survivors was 88 weeks (range: 38-163). Median PFS was 36 weeks (95% CI: 30-48); 6-month PFS rate was 65% (95% CI: 55-78). Median OS was 76 weeks (95% CI: 64-83); 52-week OS rate was 77% (95% CI: 68-88). Adjusting for age, KPS and resection extent, the current study had better PFS and OS than two UCSF historical trials (Int J Rad Oncol Biol Phys: Chang, 2004; Butowski, 2005). Preliminary results suggest PFS and OS may not be significantly improved compared to a more recent trial combining the TMZ/RT regimen with erlotinib (Prados, JCO, 2009). MGMT-methylated pts (n = 13) had longer OS (p = 0.007) and PFS (p = 0.04) than MGMT-unmethylated pts (n = 30). Pts (n = 24) with MIB index ≤ 25.3 (median) had prolonged OS (p = 0.04), but not PFS (p = 0.5) compared to pts > median (n = 27). Conclusions: The ENZ/TMZ/RT regimen was well tolerated and active in pts with GBM. Correlation of biomarkers with OS may be useful in future trials. Detailed biomarker analyses will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly Lilly

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