Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Adult; Aged; Aged, 80 and over; Aminopyridines; Antineoplastic Agents; Brain Neoplasms; Chemotherapy, Adjuvant; Disease Progression; Enzyme Activation; Female; Glioblastoma; Humans; Male; Middle Aged; Morpholines; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Progression-Free Survival; Time Factors
PURPOSE: Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.
METHODS: This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.
RESULTS: Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKT
CONCLUSION: Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.
Institute for Systems Biology
Wen, Patrick Y; Touat, Mehdi; Alexander, Brian M; Mellinghoff, Ingo K; Ramkissoon, Shakti; McCluskey, Christine S; Pelton, Kristine; Haidar, Sam; Basu, Sankha S; Gaffey, Sarah C; Brown, Loreal E; Martinez-Ledesma, Juan Emmanuel; Wu, Shaofang; Kim, Jungwoo; Wei, Wei; Park, Mi-Ae; Huse, Jason T; Kuhn, John G; Rinne, Mikael L; Colman, Howard; Agar, Nathalie Y R; Omuro, Antonio M; DeAngelis, Lisa M; Gilbert, Mark R; de Groot, John F; Cloughesy, Timothy F; Chi, Andrew S; Roberts, Thomas M; Zhao, Jean J; Lee, Eudocia Q; Nayak, Lakshmi; Heath, James R; Horky, Laura L; Batchelor, Tracy T; Beroukhim, Rameen; Chang, Susan M; Ligon, Azra H; Dunn, Ian F; Koul, Dimpy; Young, Geoffrey S; Prados, Michael D; Reardon, David A; Yung, W K Alfred; and Ligon, Keith L, "Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial." (2019). Articles, Abstracts, and Reports. 2794.