Phase II and pharmacogenomics study of enzastaurin plus temozolomide and radiation therapy in patients with glioblastoma multiforme or gliosarcoma

Abstract

2020 Background: ENZ, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ and the PI3K/AKT pathways to induce apoptosis, reduce proliferation, and suppress angiogenesis. The primary endpoint of this single-arm phase II trial was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, PK/PD, and patient-reported outcomes (PROs). A concurrent PGx project assessed the value of pretreatment molecular profiles as predictive of outcome. Magnetic resonance spectroscopy (MRS) was also evaluated during treatment for its value in predicting OS. Methods: Patients enrolled with newly diagnosed GBM/GS and 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 at 200 mg/m2 from days 1–5 of a 28-day cycle. ENZ 250 mg/day was given daily during RT and adjuvantly. Planned treatment duration was 1 year. PGx parameters were: MGMT promoter methylation, mismatch repair status, PKC isoforms, pERK, pCREB, EGFR, PTEN, GSK3B, ser9, VEGF, and pS6. MRS was performed at baseline and at scheduled intervals. Changes in molecular signatures and imaging characteristics relative to survival were estimated using Kaplan-Meier and proportional hazards models. Analyses included phase I patients at ENZ 250 mg/day. Results: From September 2007 to November 2008, 60 phase II patients enrolled; 52 completed RT and eight are receiving RT. Of these, seven patients progressed immediately after RT and 17 progressed after one or more adjuvant cycles; five discontinued due to toxicity; four withdrew from trial. Treatment was well tolerated. The only toxicities seen in more than one-third of pateints were grade 1 fatigue, grade 1 nausea, and grade 1–2 lymphopenia. Grade 1 thrombocytopenia was seen in eight patients and grade 3 lymphopenia in five patients. OS, PFS, PROs, PGx, and imaging findings will be reported. Conclusions: The combination of ENZ plus TMZ during and following RT was well tolerated and may be an active regimen in GBM. This study represents the future of neuro-oncology clinical trial design by employing a novel multi-modal therapy while concurrently studying novel imaging and molecular techniques that may predict efficacy. [Table: see text]